3dlz

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Crystal structure of human haspin in complex with AMP

Structural highlights

3dlz is a 1 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 1.85Å
Ligands:AMP, EDO, MG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HASP_HUMAN Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.[1] [2] [3] [4] [5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The protein kinase haspin/Gsg2 plays an important role in mitosis, where it specifically phosphorylates Thr-3 in histone H3 (H3T3). Its protein sequence is only weakly homologous to other protein kinases and lacks the highly conserved motifs normally required for kinase activity. Here we report structures of human haspin in complex with ATP and the inhibitor iodotubercidin. These structures reveal a constitutively active kinase conformation, stabilized by haspin-specific inserts. Haspin also has a highly atypical activation segment well adapted for specific recognition of the basic histone tail. Despite the lack of a DFG motif, ATP binding to haspin is similar to that in classical kinases; however, the ATP gamma-phosphate forms hydrogen bonds with the conserved catalytic loop residues Asp-649 and His-651, and a His651Ala haspin mutant is inactive, suggesting a direct role for the catalytic loop in ATP recognition. Enzyme kinetic data show that haspin phosphorylates substrate peptides through a rapid equilibrium random mechanism. A detailed analysis of histone modifications in the neighborhood of H3T3 reveals that increasing methylation at Lys-4 (H3K4) strongly decreases substrate recognition, suggesting a key role of H3K4 methylation in the regulation of haspin activity.

Structure and functional characterization of the atypical human kinase haspin.,Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray JW, Higgins JM, Knapp S Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20198-203. Epub 2009 Nov 16. PMID:19918057[6]

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

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Citations
20 reviews cite this structure
The structural basis for control of eukaryotic protein kinases.
Endicott et al. (2012)
19 more
78 other articles
No citations found

References

  1. ↑ Tanaka H, Iguchi N, Nakamura Y, Kohroki J, de Carvalho CE, Nishimune Y. Cloning and characterization of human haspin gene encoding haploid germ cell-specific nuclear protein kinase. Mol Hum Reprod. 2001 Mar;7(3):211-8. PMID:11228240
  2. ↑ Dai J, Sultan S, Taylor SS, Higgins JM. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 2005 Feb 15;19(4):472-88. Epub 2005 Jan 28. PMID:15681610 doi:gad.1267105
  3. ↑ Dai J, Sullivan BA, Higgins JM. Regulation of mitotic chromosome cohesion by Haspin and Aurora B. Dev Cell. 2006 Nov;11(5):741-50. PMID:17084365 doi:10.1016/j.devcel.2006.09.018
  4. ↑ Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JM. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science. 2010 Oct 8;330(6001):231-5. doi: 10.1126/science.1189435. Epub 2010 Aug , 12. PMID:20705812 doi:10.1126/science.1189435
  5. ↑ Yamagishi Y, Honda T, Tanno Y, Watanabe Y. Two histone marks establish the inner centromere and chromosome bi-orientation. Science. 2010 Oct 8;330(6001):239-43. doi: 10.1126/science.1194498. PMID:20929775 doi:10.1126/science.1194498
  6. ↑ Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray JW, Higgins JM, Knapp S. Structure and functional characterization of the atypical human kinase haspin. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20198-203. Epub 2009 Nov 16. PMID:19918057 doi:10.1073/pnas.0901989106

Contents


PDB ID 3dlz

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