4i6j

From Proteopedia

(Difference between revisions)

Revision as of 22:20, 25 December 2014

A ubiquitin ligase-substrate complex

Structural highlights

4i6j is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	4i6e, 4i6g
Gene:	Cry2, Kiaa0658 (Mus musculus), FBXL3, FBL3A, FBXL3A (Homo sapiens), SKP1, EMC19, OCP2, SKP1A, TCEB1L (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[SKP1_HUMAN] Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.^[1] ^[2] [FBXL3_HUMAN] Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation. The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2. Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex. FBXL3 probably recognizes and binds phosphorylated CRY1 and CRY2.^[3] ^[4]

Publication Abstract from PubMed

The cryptochrome (CRY) flavoproteins act as blue-light receptors in plants and insects, but perform light-independent functions at the core of the mammalian circadian clock. To drive clock oscillations, mammalian CRYs associate with the Period proteins (PERs) and together inhibit the transcription of their own genes. The SCF(FBXL3) ubiquitin ligase complex controls this negative feedback loop by promoting CRY ubiquitination and degradation. However, the molecular mechanisms of their interactions and the functional role of flavin adenine dinucleotide (FAD) binding in CRYs remain poorly understood. Here we report crystal structures of mammalian CRY2 in its apo, FAD-bound and FBXL3-SKP1-complexed forms. Distinct from other cryptochromes of known structures, mammalian CRY2 binds FAD dynamically with an open cofactor pocket. Notably, the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface. This novel F-box-protein-substrate bipartite interaction is susceptible to disruption by both FAD and PERs, suggesting a new avenue for pharmacological targeting of the complex and a multifaceted regulatory mechanism of CRY ubiquitination.

SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket.,Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N Nature. 2013 Apr 4;496(7443):64-8. doi: 10.1038/nature11964. Epub 2013 Mar 17. PMID:23503662^[5]

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

References

↑ Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005 Oct 7;20(1):9-19. PMID:16209941 doi:10.1016/j.molcel.2005.09.003
↑ Li Y, Hao B. Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase. J Biol Chem. 2010 Apr 30;285(18):13896-906. Epub 2010 Feb 24. PMID:20181953 doi:10.1074/jbc.M110.111518
↑ Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science. 2007 May 11;316(5826):900-4. Epub 2007 Apr 26. PMID:17463251 doi:10.1126/science.1141194
↑ Yoo SH, Mohawk JA, Siepka SM, Shan Y, Huh SK, Hong HK, Kornblum I, Kumar V, Koike N, Xu M, Nussbaum J, Liu X, Chen Z, Chen ZJ, Green CB, Takahashi JS. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell. 2013 Feb 28;152(5):1091-105. doi: 10.1016/j.cell.2013.01.055. PMID:23452855 doi:10.1016/j.cell.2013.01.055
↑ Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N. SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature. 2013 Apr 4;496(7443):64-8. doi: 10.1038/nature11964. Epub 2013 Mar 17. PMID:23503662 doi:http://dx.doi.org/10.1038/nature11964

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4i6j"

@@ Line 7: / Line 7: @@
 <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=4i6j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i6j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i6j RCSB], [http://www.ebi.ac.uk/pdbsum/4i6j PDBsum]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/SKP1_HUMAN SKP1_HUMAN]] Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.<ref>PMID:16209941</ref> <ref>PMID:20181953</ref>  [[http://www.uniprot.org/uniprot/FBXL3_HUMAN FBXL3_HUMAN]] Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex involved in circadian rhythm function. Plays a key role in the maintenance of both the speed and the robustness of the circadian clock oscillation. The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2. Activity of the SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex. FBXL3 probably recognizes and binds phosphorylated CRY1 and CRY2.<ref>PMID:17463251</ref> <ref>PMID:23452855</ref>
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 == Publication Abstract from PubMed ==

4i6j

From Proteopedia

Revision as of 22:20, 25 December 2014

A ubiquitin ligase-substrate complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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