User:Dzmitry Mukha/sandbox1 - Revision history

Dzmitry Mukha: spelling

2015-05-19T01:23:47Z

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←Older revision		Revision as of 01:23, 19 May 2015
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	== hnRNP A1 ==		== hnRNP A1 ==

-	'''hnRNP A1''' (alternative ~~and~~ associated names: HNRPA1, ALS19, ALS20, IBMPFD3, HNRPA1L3) is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.	+	'''hnRNP A1''' (alternative or associated names: HNRPA1, ALS19, ALS20, IBMPFD3, HNRPA1L3) is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins, and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.

	__TOC__		__TOC__
Line 17:		Line 17:

	Few natural variants of hnRNP A1 were found. Substitution		Few natural variants of hnRNP A1 were found. Substitution
-	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) was reported, but it has unknown impact on the protein function. [http://omim.org/entry/615426 ALS20 variant] carries two substitutions, D314N and N319S, in C-terminal region.	+	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) was reported, but it has an unknown impact on the protein function. [http://omim.org/entry/615426 ALS20 variant] carries two substitutions, D314N and N319S, in the C-terminal region.

-	The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do to affect RNA-binding part called UP1. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for prion-like aggregation of hnRNP A1.	+	The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do not affect RNA-binding part called UP1. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for the prion-like aggregation of hnRNP A1.

	Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.		Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.
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	=== Interaction between RRM domains ===		=== Interaction between RRM domains ===

-	RRM1 and RRM2 domains have opposite orientations in the UP1 structure and ~~they can be related by~~ an approximate twofold symmetry. Two RRMs are interaction with one another via two Arg-Asp salt bridges. <scene name='70/701439/Na_binding_1_sb1/1'>R75 interacts with D155</scene>, whereas <scene name='70/701439/Na_binding_1_sb2/1'>R88</scene> has both charge interaction and a hydrogen bond with <scene name='70/701439/Na_binding_1_sb2/1'>D157</scene>. In addition, these four amino acids interact with two water molecules stabilizing inter-domain contacts. The interactions between domains of UP1 is considered as quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice. Nevertheless, in the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.	+	RRM1 and RRM2 domains have opposite orientations in the UP1 structure, and an approximate twofold symmetry can relate them. Two RRMs are interaction with one another via two Arg-Asp salt bridges. <scene name='70/701439/Na_binding_1_sb1/1'>R75 interacts with D155</scene>, whereas <scene name='70/701439/Na_binding_1_sb2/1'>R88</scene> has both charge interaction and a hydrogen bond with <scene name='70/701439/Na_binding_1_sb2/1'>D157</scene>. In addition, these four amino acids interact with two water molecules stabilizing inter-domain contacts. The interactions between domains of UP1 is considered as quite weak since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice. Nevertheless, in the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.

	=== Nucleic acid binding ===		=== Nucleic acid binding ===
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	== Medical implications ==		== Medical implications ==

-	Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. Aggregation of hnRNP A1 drives development of [http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis amyotrophic lateral sclerosis]. Inclusion body myopathy with Paget disease (IBMPFD3) is caused by heterozygous mutation in the HNRNPA1 gene.<ref>PMID 23455423</ref>. hnRNP A1, together with septin 6, facilitate hepatitis C virus replication<ref>PMID 17229681</ref>.	+	Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. Aggregation of hnRNP A1 drives the development of [http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis amyotrophic lateral sclerosis]. Inclusion body myopathy with Paget disease (IBMPFD3) is caused by heterozygous mutation in the HNRNPA1 gene.<ref>PMID 23455423</ref>. hnRNP A1, together with septin 6, facilitate hepatitis C virus replication<ref>PMID 17229681</ref>.

	== Structures ==		== Structures ==

Dzmitry Mukha at 01:16, 19 May 2015

2015-05-19T01:16:44Z

←Older revision		Revision as of 01:16, 19 May 2015
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	=== Nucleic acid binding ===		=== Nucleic acid binding ===

-	In each RRM domain, there are two <scene name='70/701439/Na_binding_1_b1b3/1'>highly-conserved β-strands</scene>, β1 and β3.	+	In each RRM domain, there are two <scene name='70/701439/Na_binding_1_b1b3/1'>highly-conserved β-strands</scene>, β1 and β3. While the UP1 part of hnRNP A1 has a calculated isoelectric point of 8.3, electric charges are not evenly distributed on the protein surface. The β
		+	-sheet side of the protein surface is more positively charged than the α-helix side. Two conserved phenylalanines (<scene name='70/701439/Na_binding_1_phe_na/1'>F17 and F59</scene> in RRM1, and F108 and F150 in RRM2) are among the most important residues for nucleic acid binding. They participate in aromatic ring stacking with nucleic acid bases. <scene name='70/701439/Na_binding_1_phe_na/2'>F57</scene> in RRM1 and (F148 in RRM2) can bind nucleic acid backbone atoms via van der Waals contacts. In addition, there are <scene name='70/701439/Na_binding_1_phe_na/3'>three charged residues</scene> that clearly interact with nucleic acid: R55 in RRM1 (R146 in RRM2), and two charged residues located in β4 (E85 and K87 in RRM1, E176 and R178 in RRM2).

	</StructureSection>		</StructureSection>

Dzmitry Mukha at 00:30, 19 May 2015

2015-05-19T00:30:58Z

←Older revision		Revision as of 00:30, 19 May 2015
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	Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.		Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.
-
-	=== Nucleic acid binding ===
-	RRM1 and RRM2 domains have opposite orientations in the UP1 structure and they can be related by an approximate twofold symmetry. In each RRM domain, there are two <scene name='70/701439/Na_binding_1_b1b3/1'>highly-conserved β-strands</scene>, β1 and β3.

	=== Interaction between RRM domains ===		=== Interaction between RRM domains ===

-	Two RRMs are interaction with one another via two Arg-Asp salt bridges. R75 interacts with ~~R155~~, whereas R88 has both charge interaction and a hydrogen bond with ~~R157~~. The interactions between domains of UP1 is quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice. Nevertheless, in the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.	+	RRM1 and RRM2 domains have opposite orientations in the UP1 structure and they can be related by an approximate twofold symmetry. Two RRMs are interaction with one another via two Arg-Asp salt bridges. <scene name='70/701439/Na_binding_1_sb1/1'>R75 interacts with D155</scene>, whereas <scene name='70/701439/Na_binding_1_sb2/1'>R88</scene> has both charge interaction and a hydrogen bond with <scene name='70/701439/Na_binding_1_sb2/1'>D157</scene>. In addition, these four amino acids interact with two water molecules stabilizing inter-domain contacts. The interactions between domains of UP1 is considered as quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice. Nevertheless, in the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.
		+
		+	=== Nucleic acid binding ===
		+
		+	In each RRM domain, there are two <scene name='70/701439/Na_binding_1_b1b3/1'>highly-conserved β-strands</scene>, β1 and β3.

	</StructureSection>		</StructureSection>
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	== Medical implications ==		== Medical implications ==

-	Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. Aggregation of hnRNP A1 drives development of [http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis amyotrophic lateral sclerosis]. Inclusion body myopathy with Paget disease (IBMPFD3) is caused by heterozygous mutation in the HNRNPA1 gene.<ref>PMID 23455423</ref>.	+	Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. Aggregation of hnRNP A1 drives development of [http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis amyotrophic lateral sclerosis]. Inclusion body myopathy with Paget disease (IBMPFD3) is caused by heterozygous mutation in the HNRNPA1 gene.<ref>PMID 23455423</ref>. hnRNP A1, together with septin 6, facilitate hepatitis C virus replication<ref>PMID 17229681</ref>.
-		+
-	hnRNP A1, together with septin 6, facilitate hepatitis C virus replication<ref>PMID 17229681</ref>.	+

	== Structures ==		== Structures ==

Dzmitry Mukha at 00:09, 19 May 2015

2015-05-19T00:09:47Z

←Older revision		Revision as of 00:09, 19 May 2015
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	Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.		Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.

-	=== Nucleic acid binding ~~mechanism~~ ===	+	=== Nucleic acid binding ===
-	=~~== Conservative residues ===~~	+	RRM1 and RRM2 domains have opposite orientations in the UP1 structure and they can be related by an approximate twofold symmetry. In each RRM domain, there are two <scene name='70/701439/Na_binding_1_b1b3/1'>highly-conserved β-strands</scene>, β1 and β3.

	=== Interaction between RRM domains ===		=== Interaction between RRM domains ===

-	Two RRMs are interaction with one another via two Arg-Asp salt bridges. The interactions between domains of UP1 is quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice.	+	Two RRMs are interaction with one another via two Arg-Asp salt bridges. R75 interacts with R155, whereas R88 has both charge interaction and a hydrogen bond with R157. The interactions between domains of UP1 is quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice. Nevertheless, in the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.
-		+
-	In the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.	+

	</StructureSection>		</StructureSection>

Dzmitry Mukha at 23:51, 18 May 2015

2015-05-18T23:51:49Z

←Older revision		Revision as of 23:51, 18 May 2015
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-	== ~~Nucleic acid binding mechanism of~~ hnRNP A1 ==	+	== hnRNP A1 ==

-	'''hnRNP A1''' (alternative ~~gene~~ names: ALS19, ALS20~~, HNRPA1~~, IBMPFD3, HNRPA1L3) is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.	+	'''hnRNP A1''' (alternative and associated names: HNRPA1, ALS19, ALS20, IBMPFD3, HNRPA1L3) is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.

	__TOC__		__TOC__
-	== ~~Introduction~~ ==	+	== Structure overview ==
-	<StructureSection load='2UP1' size='~~340~~' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>	+	<StructureSection load='2UP1' size='480' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>
-	=== ~~Structure overview~~ ===	+	=== Introduction ===
-	Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.	+	__NOTOC__
		+	Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>. A 38-amino acid sequence at C-terminus is necessary for nuclear localization of hnRNP A1. RGG tripeptides in disordered C-terminal parts can also bind RNA.

	The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.		The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.

-	To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.	+	The structure of the protein first was studied by means of NMR in 1994<ref>PMID 8130198</ref>. To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains, which is available in PDB, was determined using a segmental labeling strategy<ref>PMID 23247503</ref>.

	=== Natural variants and isoforms ===		=== Natural variants and isoforms ===

	Few natural variants of hnRNP A1 were found. Substitution		Few natural variants of hnRNP A1 were found. Substitution
-	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) was reported, but it has unknown impact on the protein function. ALS20 variant carries two substitutions, D314N and N319S, in C-terminal region~~<ref>PMID 23455423</ref>~~.	+	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) was reported, but it has unknown impact on the protein function. [http://omim.org/entry/615426 ALS20 variant] carries two substitutions, D314N and N319S, in C-terminal region.

-	The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do to affect RNA-binding part called UP1~~<ref>PMID 15489334</ref>~~. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for prion-like aggregation of hnRNP A1~~<ref>PMID 23455423</ref>~~.	+	The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do to affect RNA-binding part called UP1. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for prion-like aggregation of hnRNP A1.

-	Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>15161980</ref>.	+	Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>PMID 15161980</ref>.
-	~~</StructureSection>~~	+

-	== ~~Binding~~ mechanism ==	+	=== Nucleic acid binding mechanism ===
		+	=== Conservative residues ===

-		+	=== Interaction between RRM domains ===
-		+
-	=~~= Conservative residues ==~~	+
-		+
-	== Interaction between RRM domains ==	+

	Two RRMs are interaction with one another via two Arg-Asp salt bridges. The interactions between domains of UP1 is quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice.		Two RRMs are interaction with one another via two Arg-Asp salt bridges. The interactions between domains of UP1 is quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice.
Line 35:		Line 32:
	In the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.		In the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.

-	~~== Protein-protein interactions ==~~	+	</StructureSection>

		+	== Medical implications ==

-	~~== Medical implications ==~~	+	Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. Aggregation of hnRNP A1 drives development of [http://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis amyotrophic lateral sclerosis]. Inclusion body myopathy with Paget disease (IBMPFD3) is caused by heterozygous mutation in the HNRNPA1 gene.<ref>PMID 23455423</ref>.

-	~~Incorporation of~~ hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, ~~brain~~, ~~motor neuron and bone~~<ref>PMID ~~23455423~~</ref>.	+	hnRNP A1, together with septin 6, facilitate hepatitis C virus replication<ref>PMID 17229681</ref>.

	== Structures ==		== Structures ==

Dzmitry Mukha at 22:57, 18 May 2015

2015-05-18T22:57:37Z

←Older revision		Revision as of 22:57, 18 May 2015
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	__TOC__		__TOC__
-	== ~~Structure overview~~ ==	+	== Introduction ==
	<StructureSection load='2UP1' size='340' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>		<StructureSection load='2UP1' size='340' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>
		+	=== Structure overview ===
	Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.		Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.

Line 15:		Line 16:

	Few natural variants of hnRNP A1 were found. Substitution		Few natural variants of hnRNP A1 were found. Substitution
-	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) has unknown impact on the protein function. ALS20 carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.	+	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) was reported, but it has unknown impact on the protein function. ALS20 variant carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.

	The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do to affect RNA-binding part called UP1<ref>PMID 15489334</ref>. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for prion-like aggregation of hnRNP A1<ref>PMID 23455423</ref>.		The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do to affect RNA-binding part called UP1<ref>PMID 15489334</ref>. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for prion-like aggregation of hnRNP A1<ref>PMID 23455423</ref>.
Line 35:		Line 36:

	== Protein-protein interactions ==		== Protein-protein interactions ==
		+

	== Medical implications ==		== Medical implications ==
		+
		+	Incorporation of hnRNP A1 into stress granules drives the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Dysregulated polymerization caused by a potent mutant steric zipper motif in a disordered C-terminal region can initiate degenerative disease. hnRNP A1 is considered as one of the candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone<ref>PMID 23455423</ref>.

	== Structures ==		== Structures ==
Line 62:		Line 66:
	<references/>		<references/>

-	[[Category:Transcription\|Transcription]]	+	<!--[[Category:Transcription\|Transcription]]
-	[[Category:Rna processing \|RNA Processing]]	+	[[Category:Rna processing \|RNA Processing]] -->

Dzmitry Mukha at 22:47, 18 May 2015

2015-05-18T22:47:35Z

←Older revision		Revision as of 22:47, 18 May 2015
Line 6:		Line 6:
	== Structure overview ==		== Structure overview ==
	<StructureSection load='2UP1' size='340' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>		<StructureSection load='2UP1' size='340' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>
-	Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region ~~(residues 315 – 341)~~ is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.	+	Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.

	The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.		The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.

	To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.		To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.
-
-	=== Post-translational modifications ===

	=== Natural variants and isoforms ===		=== Natural variants and isoforms ===
Line 19:		Line 17:
	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) has unknown impact on the protein function. ALS20 carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.		<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) has unknown impact on the protein function. ALS20 carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.

-	~~Isoforms identified for~~ hnRNP A1 have deletions in disordered C-terminal regions ~~(residues 203 – 307 and 252 – 303) and~~ do to affect RNA-binding UP1<ref>PMID 15489334</ref>.	+	The ORF of hnRNP A1 encodes 372 amino acids. In the primary isoform A1-1 residues 252 – 303 are missing. This isoform is twenty times more abundant than isoform A1-B having all amino acid residues. Isoform 2 lacks residues 203 – 307. Isoform A1-1 and isoform 2 have deletions in disordered C-terminal regions. These deletions do to affect RNA-binding part called UP1<ref>PMID 15489334</ref>. It was shown that some of the residues in the region, which is absent in the primary isoform, are responsible for prion-like aggregation of hnRNP A1<ref>PMID 23455423</ref>.

		+	Residues R194, R206 and R225 of hnRNP A1 undergo methylation by two methyl groups, probably to asymmetric dimethylarginine. hnRNP A1 is sumoylated<ref>15161980</ref>.
	</StructureSection>		</StructureSection>

	== Binding mechanism ==		== Binding mechanism ==
		+
		+

	== Conservative residues ==		== Conservative residues ==

Dzmitry Mukha at 22:19, 18 May 2015

2015-05-18T22:19:40Z

←Older revision		Revision as of 22:19, 18 May 2015
Line 16:		Line 16:
	=== Natural variants and isoforms ===		=== Natural variants and isoforms ===

-	Few natural variants of hnRNP A1 were found. Substitution <scene name='70/701439/~~Hnrnpa1_f1_s73~~/2'>N73S</scene> (rs6533) has unknown impact on the protein function. ALS20 carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.	+	Few natural variants of hnRNP A1 were found. Substitution
		+	<scene name='70/701439/Na_binding_1_n73/1'>N73S</scene> ([http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?type=rs&rs=6533 rs6533]) has unknown impact on the protein function. ALS20 carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.

	Isoforms identified for hnRNP A1 have deletions in disordered C-terminal regions (residues 203 – 307 and 252 – 303) and do to affect RNA-binding UP1<ref>PMID 15489334</ref>.		Isoforms identified for hnRNP A1 have deletions in disordered C-terminal regions (residues 203 – 307 and 252 – 303) and do to affect RNA-binding UP1<ref>PMID 15489334</ref>.

Dzmitry Mukha at 22:11, 18 May 2015

2015-05-18T22:11:00Z

←Older revision		Revision as of 22:11, 18 May 2015
Line 6:		Line 6:
	== Structure overview ==		== Structure overview ==
	<StructureSection load='2UP1' size='340' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>		<StructureSection load='2UP1' size='340' side='right' caption='Human hnRNP A1 structure overview' scene='70/701439/Na_binding_1/1'>
-	Human hnRNP A1 consists of 320 amino acids. N-terminal region is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region (residues 315 – 341) is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.	+	Human hnRNP A1 consists of 320 amino acids. <scene name='70/701439/Na_binding_1/1'>N-terminal region</scene> is composed of two RNA recognition motifs (RRM) followed by highly flexible C-terminal glycine-rich region. The structure of disordered C-terminal region which contains 45 % of glycine in its sequence has not been resolved till now. However, a short peptide from C-terminal region (residues 315 – 341) is available in the structure of <scene name='70/701439/H24m_hnpart/1'>transportin bound to hnRNP A1</scene> (2H4M). <scene name='70/701439/Na_domain1/1'>RRM1</scene> and <scene name='70/701439/Na_binding_2/1'>RRM2</scene> (together span residues 1 to 196) form <scene name='70/701439/Na_binding_1/1'>unwinding protein 1 (UP1)</scene>.

	The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.		The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.
Line 12:		Line 12:
	To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.		To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.

		+	=== Post-translational modifications ===

		+	=== Natural variants and isoforms ===

-	=~~== Post~~-~~translational modifications ===~~	+	Few natural variants of hnRNP A1 were found. Substitution <scene name='70/701439/Hnrnpa1_f1_s73/2'>N73S</scene> (rs6533) has unknown impact on the protein function. ALS20 carries two substitutions, D314N and N319S, in C-terminal region<ref>PMID 23455423</ref>.
		+
		+	Isoforms identified for hnRNP A1 have deletions in disordered C-terminal regions (residues 203 – 307 and 252 – 303) and do to affect RNA-binding UP1<ref>PMID 15489334</ref>.

	</StructureSection>		</StructureSection>

Dzmitry Mukha: draft

2015-05-18T21:37:39Z

draft

←Older revision		Revision as of 21:37, 18 May 2015
Line 1:		Line 1:
	== Nucleic acid binding mechanism of hnRNP A1 ==		== Nucleic acid binding mechanism of hnRNP A1 ==

-	'''hnRNP A1''' is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.	+	'''hnRNP A1''' (alternative gene names: ALS19, ALS20, HNRPA1, IBMPFD3, HNRPA1L3) is a member of A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). hnRNP A1 is involved in the packaging of premature mRNA into hnRNP particles and transport of poly(A) mRNA from the nucleus to the cytoplasm. hnRNP A1 has been characterized as a component of protein complexes bound to premature mRNA (hnRNP complexes). hnRNP A1 is one of the most abundant and best-characterized components of hnRNP complexes. Human hnRNP functions also in telomere length regulation and miRNA biogenesis. It may play a role in the replication of RNA viruses.

	__TOC__		__TOC__
Line 10:		Line 10:
	The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.		The secondary structure of the RRM is characterized by a βαβαββαβ-fold in which the four β-strands make an anti-parallel β-sheet that forms most of the nucleic acid binding surface.

-	To date, several crystal structures of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.	+	To date, several [[#Structures\|crystal structures]] of UP1 have been solved both in their free form and bound to repeats of telomeric DNA fragments <ref>PMID 9115444</ref><ref>PMID 11917013</ref><ref>PMID 10323862</ref><ref>PMID 12904298</ref><ref>PMID 15342234</ref>. NMR structure of hnRNP A1 RRM domains was determined using a segmental labeling strategy <ref>PMID 23247503</ref>.
		+
		+
		+
		+	=== Post-translational modifications ===
		+
	</StructureSection>		</StructureSection>

-	== Binding ==	+	== Binding mechanism ==

	== Conservative residues ==		== Conservative residues ==
Line 19:		Line 24:
	== Interaction between RRM domains ==		== Interaction between RRM domains ==

-	Two RRMs are interaction with one another via two Arg-Asp salt bridges. The interactions between domains of UP1 is quite ~~week~~, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice.	+	Two RRMs are interaction with one another via two Arg-Asp salt bridges. The interactions between domains of UP1 is quite weak, since the orientation of the two RRMs can be influenced by nucleic acid binding or by contacts with neighboring molecules in the crystal lattice.

	In the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.		In the solution structure of free UP1, the two Arg-Asp salt bridges are conserved at the interface between RRM1 and RRM2.

-	== ==	+	== Protein-protein interactions ==
		+
		+	== Medical implications ==
		+
		+	== Structures ==
		+	=== X-ray ===
		+	* [[1ha1]]
		+	* [[1l3k]]
		+	* [[1pgz]]
		+	* [[1po6]]
		+	* [[1u1k]]
		+	* [[1u1l]]
		+	* [[1u1m]]
		+	* [[1u1n]]
		+	* [[1u1o]]
		+	* [[1u1p]]
		+	* [[1u1q]]
		+	* [[1u1r]]
		+	* [[1up1]]
		+	* [[2h4m]]
		+	* [[2up1]]
		+
		+	=== Solution NMR ===
		+	* [[2lyv]]

	== References ==		== References ==
	<references/>		<references/>
		+
		+	[[Category:Transcription\|Transcription]]
		+	[[Category:Rna processing \|RNA Processing]]