3t1n

From Proteopedia

(Difference between revisions)

Current revision

Structure of human MICROCEPHALIN (MCPH1) TANDEM BRCT domains in complex with a CDC27 phosphopeptide

Structural highlights

3t1n is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MCPH1_HUMAN Premature chromosome condensation with microcephaly and intellectual deficit;Autosomal recessive primary microcephaly. Defects in MCPH1 are the cause of microcephaly primary type 1 (MCPH1) [MIM:251200; also known as true microcephaly or microcephaly vera. Microcephaly is defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits. This entity is inherited as autosomal recessive trait.^[1] ^[2] ^[3]

Function

MCPH1_HUMAN Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.^[4] ^[5] ^[6]

Publication Abstract from PubMed

Microcephalin (MCPH1), the first gene identified as causative for primary recessive autosomal microcephaly, is aberrantly expressed in autism-like disorders and human malignancy of breast and ovarian origin. MCPH1, the encoded protein product, has been implicated in various cellular processes including the DNA damage checkpoint, DNA repair and transcription. While our understanding of the cellular context in which MCPH1 operates continues to develop, a structural understanding of the C-terminal tandem BRCT domains of MCPH1 remains unexplored. Here, we identify Cdc27, a component of the anaphase-promoting complex (APC/C), as a novel interacting partner of MCPH1. We provide in vitro and in vivo evidence that the C-terminal tandem BRCT domains of MCPH1 (C-BRCTs) bind Cdc27 in a phosphorylation-dependent manner. To further characterize this interaction, we determined the structure of MCPH1 C-BRCTs in complex with a phosphorylated Cdc27 peptide (pCdc27) using X-ray crystallography. Based on this structure, we identified single amino acid mutations targeted at the binding interface that disrupted the MCPH1-pCdc27 interaction. Collectively, our data define the biochemical, structural and cellular determinants of the novel interaction between MCPH1 and Cdc27 and suggest that this interaction may occur within the larger context of MCPH1-APC/C.

Molecular basis for the association of microcephalin (MCPH1) with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex.,Singh N, Wiltshire T, Thompson JR, Mer G, Couch FJ J Biol Chem. 2011 Dec 2. PMID:22139841^[7]

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

References

↑ Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002 Jul;71(1):136-42. Epub 2002 Jun 3. PMID:12046007 doi:10.1086/341283
↑ Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004 Aug;75(2):261-6. Epub 2004 Jun 15. PMID:15199523 doi:10.1086/422855
↑ Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D, Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G, Neitzel H. The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Hum Mutat. 2005 Nov;26(5):496. PMID:16211557 doi:10.1002/humu.9382
↑ Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002 Jul;71(1):136-42. Epub 2002 Jun 3. PMID:12046007 doi:10.1086/341283
↑ Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004 Aug;75(2):261-6. Epub 2004 Jun 15. PMID:15199523 doi:10.1086/422855
↑ Xu X, Lee J, Stern DF. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J Biol Chem. 2004 Aug 13;279(33):34091-4. Epub 2004 Jun 25. PMID:15220350 doi:10.1074/jbc.C400139200
↑ Singh N, Wiltshire T, Thompson JR, Mer G, Couch FJ. Molecular basis for the association of microcephalin (MCPH1) with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex. J Biol Chem. 2011 Dec 2. PMID:22139841 doi:10.1074/jbc.M111.307868

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/3t1n"

Categories: Homo sapiens | Large Structures | Mer G | Singh N | Thompson JR

@@ Line 1: / Line 1: @@
-[[Image:3t1n.jpg|left|200px]]
-<!--
+==Structure of human MICROCEPHALIN (MCPH1) TANDEM BRCT domains in complex with a CDC27 phosphopeptide==
-The line below this paragraph, containing "STRUCTURE_3t1n", creates the "Structure Box" on the page.
+<StructureSection load='3t1n' size='340' side='right'caption='[[3t1n]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3t1n]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T1N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T1N FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
-{{STRUCTURE_3t1n|  PDB=3t1n  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3t1n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t1n OCA], [https://pdbe.org/3t1n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t1n RCSB], [https://www.ebi.ac.uk/pdbsum/3t1n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t1n ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/MCPH1_HUMAN MCPH1_HUMAN] Premature chromosome condensation with microcephaly and intellectual deficit;Autosomal recessive primary microcephaly. Defects in MCPH1 are the cause of microcephaly primary type 1 (MCPH1) [MIM:[https://omim.org/entry/251200 251200]; also known as true microcephaly or microcephaly vera. Microcephaly is defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits. This entity is inherited as autosomal recessive trait.<ref>PMID:12046007</ref> <ref>PMID:15199523</ref> <ref>PMID:16211557</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/MCPH1_HUMAN MCPH1_HUMAN] Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.<ref>PMID:12046007</ref> <ref>PMID:15199523</ref> <ref>PMID:15220350</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Microcephalin (MCPH1), the first gene identified as causative for primary recessive autosomal microcephaly, is aberrantly expressed in autism-like disorders and human malignancy of breast and ovarian origin. MCPH1, the encoded protein product, has been implicated in various cellular processes including the DNA damage checkpoint, DNA repair and transcription. While our understanding of the cellular context in which MCPH1 operates continues to develop, a structural understanding of the C-terminal tandem BRCT domains of MCPH1 remains unexplored. Here, we identify Cdc27, a component of the anaphase-promoting complex (APC/C), as a novel interacting partner of MCPH1. We provide in vitro and in vivo evidence that the C-terminal tandem BRCT domains of MCPH1 (C-BRCTs) bind Cdc27 in a phosphorylation-dependent manner. To further characterize this interaction, we determined the structure of MCPH1 C-BRCTs in complex with a phosphorylated Cdc27 peptide (pCdc27) using X-ray crystallography. Based on this structure, we identified single amino acid mutations targeted at the binding interface that disrupted the MCPH1-pCdc27 interaction. Collectively, our data define the biochemical, structural and cellular determinants of the novel interaction between MCPH1 and Cdc27 and suggest that this interaction may occur within the larger context of MCPH1-APC/C.
-===Structure of human MICROCEPHALIN (MCPH1) TANDEM BRCT domains in complex with a CDC27 phosphopeptide===
+Molecular basis for the association of microcephalin (MCPH1) with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex.,Singh N, Wiltshire T, Thompson JR, Mer G, Couch FJ J Biol Chem. 2011 Dec 2. PMID:22139841<ref>PMID:22139841</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-==About this Structure==
+</div>
-[[3t1n]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T1N OCA].
+<div class="pdbe-citations 3t1n" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Mer, G.]]
+[[Category: Large Structures]]
-[[Category: Singh, N.]]
+[[Category: Mer G]]
-[[Category: Thompson, J R.]]
+[[Category: Singh N]]
-[[Category: Cell cycle regulation]]
+[[Category: Thompson JR]]
-[[Category: Cell cycle-peptide complex]]
-[[Category: Dna repair]]
-[[Category: Mitosis]]
-[[Category: Phosphorylation]]
-[[Category: Tandem brct domain]]

3t1n

From Proteopedia

Current revision

Structure of human MICROCEPHALIN (MCPH1) TANDEM BRCT domains in complex with a CDC27 phosphopeptide

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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