6o1q

From Proteopedia

(Difference between revisions)

Revision as of 16:41, 14 August 2019

The N-terminal domain of NPHP1 folds into an antiparallel three-stranded coiled coil

Structural highlights

6o1q is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[NPHP1_HUMAN] Defects in NPHP1 are the cause of nephronophthisis type 1 (NPHP1) [MIM:256100]; also known as familial juvenile nephronophthisis 1. NPHP1 is an autosomal recessive inherited disease characterized by anemia, polyuria, polydipsia, isosthenuria and death in uremia. Symmetrical destruction of the kidneys involving both tubules and glomeruli occurs. The underlying pathology is a chronic tubulo-interstitial nephropathy with characteristic tubular basement membrane thickening and medullary cyst formation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. The age at death ranges from about 4 to 15 years.^[1] Defects in NPHP1 are the cause of Senior-Loken syndrome type 1 (SLSN1) [MIM:266900]; also known as juvenile nephronophthisis with Leber amaurosis. SLSN is a renal-retinal disorder characterized by progressive wasting of the filtering unit of the kidney, with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life.^[2] Defects in NPHP1 are the cause of Joubert syndrome type 4 (JBTS4) [MIM:609583]. JBTS is an autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. JBTS4 is a phenotypically mild form.^[3]

Function

[NPHP1_HUMAN] Together with BCAR1 it may play a role in the control of epithelial cell polarity. Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling. May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development. In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis (By similarity).

Publication Abstract from PubMed

Mutations in the NPHP1 gene, coding for human nephrocystin-1 (NPHP1), cause the autosomal recessive disease nephronophthisis, the most common cause of end-stage renal disease in children and adolescents. The function and structure of NPHP1 are still poorly characterized. NPHP1 presents a modular structure well in keeping with its role as an adaptor protein: it harbors an SH3 domain flanked by two glutamic acid-rich regions and a conserved C-terminal nephrocystin homology domain (NHD). Similar to other NPHP protein family members, its N-terminus contains a putative coiled-coil domain (NPHP1CC) that is supposed to play an important role in NPHP1 self-association and/or protein-protein interactions. Structural studies proving its structure and its oligomerization state are still lacking. Here we demonstrate that NPHP1CC is monomeric in solution and unexpectedly folds into an autonomous domain forming a three-stranded antiparallel coiled coil suitable for protein-protein interactions. Notably, we found that the NPHP1CC shares remarkable structural similarities with the three-stranded coiled coil of the BAG domain protein family, which is known to mediate the anti-apoptotic function of these proteins, suggesting a possible similar role for NPHP1CC. In agreement with this hypothesis, we show that in the context of the full-length protein the NPHP1CC is fundamental to regulate resistance to apoptotic stimuli.

The N-Terminal Domain of NPHP1 Folds into a Monomeric Left-Handed Antiparallel Three-Stranded Coiled Coil with Anti-apoptotic Function.,Mannella V, Quilici G, Nigro EA, Lampis M, Minici C, Degano M, Boletta A, Musco G ACS Chem Biol. 2019 Aug 5. doi: 10.1021/acschembio.9b00582. PMID:31345020^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Betz R, Rensing C, Otto E, Mincheva A, Zehnder D, Lichter P, Hildebrandt F. Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J Pediatr. 2000 Jun;136(6):828-31. PMID:10839884
↑ Caridi G, Murer L, Bellantuono R, Sorino P, Caringella DA, Gusmano R, Ghiggeri GM. Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis. 1998 Dec;32(6):1059-62. PMID:9856524
↑ Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, McDonald R, Eddy A, Chance PF, Glass IA. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet. 2004 Jul;75(1):82-91. Epub 2004 May 11. PMID:15138899 doi:10.1086/421846
↑ Mannella V, Quilici G, Nigro EA, Lampis M, Minici C, Degano M, Boletta A, Musco G. The N-Terminal Domain of NPHP1 Folds into a Monomeric Left-Handed Antiparallel Three-Stranded Coiled Coil with Anti-apoptotic Function. ACS Chem Biol. 2019 Aug 5. doi: 10.1021/acschembio.9b00582. PMID:31345020 doi:http://dx.doi.org/10.1021/acschembio.9b00582

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6o1q"

Categories: Large Structures | Mannella, V | Musco, G | Apoptosis | Nephronophthisis

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6o1q is ON HOLD  until Paper Publication
+==The N-terminal domain of NPHP1 folds into an antiparallel three-stranded coiled coil==
+<StructureSection load='6o1q' size='340' side='right'caption='[[6o1q]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6o1q]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O1Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O1Q FirstGlance]. <br>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o1q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o1q OCA], [http://pdbe.org/6o1q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o1q RCSB], [http://www.ebi.ac.uk/pdbsum/6o1q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o1q ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/NPHP1_HUMAN NPHP1_HUMAN]] Defects in NPHP1 are the cause of nephronophthisis type 1 (NPHP1) [MIM:[http://omim.org/entry/256100 256100]]; also known as familial juvenile nephronophthisis 1. NPHP1 is an autosomal recessive inherited disease characterized by anemia, polyuria, polydipsia, isosthenuria and death in uremia. Symmetrical destruction of the kidneys involving both tubules and glomeruli occurs. The underlying pathology is a chronic tubulo-interstitial nephropathy with characteristic tubular basement membrane thickening and medullary cyst formation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. The age at death ranges from about 4 to 15 years.<ref>PMID:10839884</ref>   Defects in NPHP1 are the cause of Senior-Loken syndrome type 1 (SLSN1) [MIM:[http://omim.org/entry/266900 266900]]; also known as juvenile nephronophthisis with Leber amaurosis. SLSN is a renal-retinal disorder characterized by progressive wasting of the filtering unit of the kidney, with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life.<ref>PMID:9856524</ref>   Defects in NPHP1 are the cause of Joubert syndrome type 4 (JBTS4) [MIM:[http://omim.org/entry/609583 609583]]. JBTS is an autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. JBTS4 is a phenotypically mild form.<ref>PMID:15138899</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/NPHP1_HUMAN NPHP1_HUMAN]] Together with BCAR1 it may play a role in the control of epithelial cell polarity. Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling. May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development. In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mutations in the NPHP1 gene, coding for human nephrocystin-1 (NPHP1), cause the autosomal recessive disease nephronophthisis, the most common cause of end-stage renal disease in children and adolescents. The function and structure of NPHP1 are still poorly characterized. NPHP1 presents a modular structure well in keeping with its role as an adaptor protein: it harbors an SH3 domain flanked by two glutamic acid-rich regions and a conserved C-terminal nephrocystin homology domain (NHD). Similar to other NPHP protein family members, its N-terminus contains a putative coiled-coil domain (NPHP1CC) that is supposed to play an important role in NPHP1 self-association and/or protein-protein interactions. Structural studies proving its structure and its oligomerization state are still lacking. Here we demonstrate that NPHP1CC is monomeric in solution and unexpectedly folds into an autonomous domain forming a three-stranded antiparallel coiled coil suitable for protein-protein interactions. Notably, we found that the NPHP1CC shares remarkable structural similarities with the three-stranded coiled coil of the BAG domain protein family, which is known to mediate the anti-apoptotic function of these proteins, suggesting a possible similar role for NPHP1CC. In agreement with this hypothesis, we show that in the context of the full-length protein the NPHP1CC is fundamental to regulate resistance to apoptotic stimuli.
-Authors: Musco, G., Mannella, V.
+The N-Terminal Domain of NPHP1 Folds into a Monomeric Left-Handed Antiparallel Three-Stranded Coiled Coil with Anti-apoptotic Function.,Mannella V, Quilici G, Nigro EA, Lampis M, Minici C, Degano M, Boletta A, Musco G ACS Chem Biol. 2019 Aug 5. doi: 10.1021/acschembio.9b00582. PMID:31345020<ref>PMID:31345020</ref>
-Description: The N-terminal domain of NPHP1 folds into an antiparallel three-stranded coiled coil
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6o1q" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Mannella, V]]
 [[Category: Musco, G]]
+[[Category: Apoptosis]]
+[[Category: Nephronophthisis]]

6o1q

From Proteopedia

Revision as of 16:41, 14 August 2019

The N-terminal domain of NPHP1 folds into an antiparallel three-stranded coiled coil

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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