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4drb

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The crystal structure of FANCM bound MHF complexThe crystal structure of FANCM bound MHF complex

Structural highlights

4drb is a 15 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Gene:APITD1, CENPS, FAAP16, MHF1 (HUMAN), FANCM, KIAA1596 (HUMAN), STRA13, CENPX, FAAP10, MHF2 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FANCM_HUMAN] Fanconi anemia. The disease is caused by mutations affecting the gene represented in this entry.

Function

[CENPS_HUMAN] DNA-binding component of the FA core complex involved in DNA damage repair and genome maintenance. Required for optimal chromatin association of the FA core complex. Required for efficient damage-induced monoubiquitination and focus formation of FANCD2. Stabilizes FAAD24, FANCM and STRA13/CENPX in the FA core complex. Plays a role in DNA interstrand cross-linking (ICL) repair and in recovery of replication forks stalled by topoisomerase I-DNA cleavage intermediates induced by camptothecin. Component of the heterotetrameric CENP-T-W-S-X complex that binds and supercoils DNA, and plays an important role in kinetochore assembly. Component of the APITD1/CENPS complex that is essential for the stable assembly of the outer kinetochore. Plays an important role in mitotic progression and chromosome segregation. Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation.[1] [2] [REFERENCE:8] [CENPX_HUMAN] DNA-binding component of the FA core complex involved in DNA damage repair and genome maintenance. Recruited to forks stalled by DNA interstrand cross-links, and required for cellular resistance to such lesions. Component of the heterotetrameric CENP-T-W-S-X complex that binds and supercoils DNA, and plays an important role in kinetochore assembly. Component of the APITD1/CENPS complex that is essential for the stable assembly of the outer kinetochore. Plays an important role in mitotic progression and chromosome segregation.[3] [4] [REFERENCE:6] [FANCM_HUMAN] ATPase required for FANCD2 ubiquitination, a key reaction in DNA repair. Binds to ssDNA but not to dsDNA. Recruited to forks stalled by DNA interstrand cross-links, and required for cellular resistance to such lesions.[5] [6] [REFERENCE:7][REFERENCE:8]

Publication Abstract from PubMed

Fanconi anaemia is a rare genetic disease characterized by chromosomal instability and cancer susceptibility. The Fanconi anaemia complementation group protein M (FANCM) forms an evolutionarily conserved DNA-processing complex with MHF1/MHF2 (histone-fold-containing proteins), which is essential for DNA repair in response to genotoxic stress. Here we present the crystal structures of the MHF1-MHF2 complex alone and bound to a fragment of FANCM (FANCM(661-800), designated FANCM-F). The structures show that MHF1 and MHF2 form a compact tetramer to which FANCM-F binds through a 'dual-V' shaped structure. FANCM-F and (MHF1-MHF2)(2) cooperate to constitute a new DNA-binding site that is coupled to the canonical L1L2 region. Perturbation of the MHF-FANCM-F structural plasticity changes the localization of FANCM in vivo. The MHF-FANCM interaction and its subcellular localization are altered by a disease-associated mutant of FANCM. These findings reveal the molecular basis of MHF-FANCM recognition and provide mechanistic insights into the pathway leading to Fanconi anaemia.

The structure of the FANCM-MHF complex reveals physical features for functional assembly.,Tao Y, Jin C, Li X, Qi S, Chu L, Niu L, Yao X, Teng M Nat Commun. 2012 Apr 17;3:782. doi: 10.1038/ncomms1779. PMID:22510687[7]

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

See Also

References

  1. ↑ Amano M, Suzuki A, Hori T, Backer C, Okawa K, Cheeseman IM, Fukagawa T. The CENP-S complex is essential for the stable assembly of outer kinetochore structure. J Cell Biol. 2009 Jul 27;186(2):173-82. doi: 10.1083/jcb.200903100. Epub 2009 Jul, 20. PMID:19620631 doi:http://dx.doi.org/10.1083/jcb.200903100
  2. ↑ Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R. N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi:, 10.1073/pnas.1210303109. Epub 2012 Jul 18. PMID:22814378 doi:http://dx.doi.org/10.1073/pnas.1210303109
  3. ↑ Amano M, Suzuki A, Hori T, Backer C, Okawa K, Cheeseman IM, Fukagawa T. The CENP-S complex is essential for the stable assembly of outer kinetochore structure. J Cell Biol. 2009 Jul 27;186(2):173-82. doi: 10.1083/jcb.200903100. Epub 2009 Jul, 20. PMID:19620631 doi:http://dx.doi.org/10.1083/jcb.200903100
  4. ↑ Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R. N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi:, 10.1073/pnas.1210303109. Epub 2012 Jul 18. PMID:22814378 doi:http://dx.doi.org/10.1073/pnas.1210303109
  5. ↑ Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005 Sep;37(9):958-63. Epub 2005 Aug 21. PMID:16116422 doi:ng1626
  6. ↑ Mosedale G, Niedzwiedz W, Alpi A, Perrina F, Pereira-Leal JB, Johnson M, Langevin F, Pace P, Patel KJ. The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway. Nat Struct Mol Biol. 2005 Sep;12(9):763-71. Epub 2005 Aug 21. PMID:16116434 doi:10.1038/nsmb981
  7. ↑ Tao Y, Jin C, Li X, Qi S, Chu L, Niu L, Yao X, Teng M. The structure of the FANCM-MHF complex reveals physical features for functional assembly. Nat Commun. 2012 Apr 17;3:782. doi: 10.1038/ncomms1779. PMID:22510687 doi:10.1038/ncomms1779

4drb, resolution 2.63Å

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