4k92

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A Cryptic TOG Domain with a Distinct Architecture Underlies CLASP-Dependent Bipolar Spindle Formation

Structural highlights

4k92 is a 2 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 2.005Å
Ligands:MSE
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CLAP1_HUMAN Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules. Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2. This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle.[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

CLASP is a key regulator of microtubule (MT) dynamics and bipolar mitotic spindle structure with CLASP mutants displaying a distinctive monopolar spindle phenotype. It has been postulated that cryptic TOG domains underlie CLASP's ability to regulate MT dynamics. Here, we report the crystal structure of a cryptic TOG domain (TOG2) from human CLASP1, demonstrating the presence of a TOG array in the CLASP family. Strikingly, CLASP1 TOG2 exhibits a convex architecture across the tubulin-binding surface that contrasts with the flat tubulin-binding surface of XMAP215 family TOG domains. Mutations in key conserved TOG2 determinants abrogate the ability of CLASP mutants to rescue bipolar spindle formation in Drosophila cells depleted of endogenous CLASP. These findings highlight the common mechanistic use of TOG domains in XMAP215 and CLASP families to regulate MT dynamics and suggest that differential TOG domain architecture may confer distinct functions to these critical cytoskeletal regulators.

A Cryptic TOG Domain with a Distinct Architecture Underlies CLASP-Dependent Bipolar Spindle Formation.,Leano JB, Rogers SL, Slep KC Structure. 2013 May 29. pii: S0969-2126(13)00130-5. doi:, 10.1016/j.str.2013.04.018. PMID:23727231[7]

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

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References

  1. ↑ Akhmanova A, Hoogenraad CC, Drabek K, Stepanova T, Dortland B, Verkerk T, Vermeulen W, Burgering BM, De Zeeuw CI, Grosveld F, Galjart N. Clasps are CLIP-115 and -170 associating proteins involved in the regional regulation of microtubule dynamics in motile fibroblasts. Cell. 2001 Mar 23;104(6):923-35. PMID:11290329
  2. ↑ Maiato H, Fairley EA, Rieder CL, Swedlow JR, Sunkel CE, Earnshaw WC. Human CLASP1 is an outer kinetochore component that regulates spindle microtubule dynamics. Cell. 2003 Jun 27;113(7):891-904. PMID:12837247
  3. ↑ Mimori-Kiyosue Y, Grigoriev I, Lansbergen G, Sasaki H, Matsui C, Severin F, Galjart N, Grosveld F, Vorobjev I, Tsukita S, Akhmanova A. CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex. J Cell Biol. 2005 Jan 3;168(1):141-53. PMID:15631994 doi:10.1083/jcb.200405094
  4. ↑ Mimori-Kiyosue Y, Grigoriev I, Sasaki H, Matsui C, Akhmanova A, Tsukita S, Vorobjev I. Mammalian CLASPs are required for mitotic spindle organization and kinetochore alignment. Genes Cells. 2006 Aug;11(8):845-57. PMID:16866869 doi:GTC990
  5. ↑ Pereira AL, Pereira AJ, Maia AR, Drabek K, Sayas CL, Hergert PJ, Lince-Faria M, Matos I, Duque C, Stepanova T, Rieder CL, Earnshaw WC, Galjart N, Maiato H. Mammalian CLASP1 and CLASP2 cooperate to ensure mitotic fidelity by regulating spindle and kinetochore function. Mol Biol Cell. 2006 Oct;17(10):4526-42. Epub 2006 Aug 16. PMID:16914514 doi:E06-07-0579
  6. ↑ Efimov A, Kharitonov A, Efimova N, Loncarek J, Miller PM, Andreyeva N, Gleeson P, Galjart N, Maia AR, McLeod IX, Yates JR 3rd, Maiato H, Khodjakov A, Akhmanova A, Kaverina I. Asymmetric CLASP-dependent nucleation of noncentrosomal microtubules at the trans-Golgi network. Dev Cell. 2007 Jun;12(6):917-30. PMID:17543864 doi:10.1016/j.devcel.2007.04.002
  7. ↑ Leano JB, Rogers SL, Slep KC. A Cryptic TOG Domain with a Distinct Architecture Underlies CLASP-Dependent Bipolar Spindle Formation. Structure. 2013 May 29. pii: S0969-2126(13)00130-5. doi:, 10.1016/j.str.2013.04.018. PMID:23727231 doi:10.1016/j.str.2013.04.018

Contents


PDB ID 4k92

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