Proteopedia

8whl

Crystal structure of CLASP2 in complex with CENP-ECrystal structure of CLASP2 in complex with CENP-E

Structural highlights

8whl is a 8 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 3.2Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CLAP2_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. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex.[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Microtubule organization in cells relies on targeting mechanisms. Cytoplasmic linker proteins (CLIPs) and CLIP-associated proteins (CLASPs) are key regulators of microtubule organization, yet the underlying mechanisms remain elusive. Here, we reveal that the C-terminal domain of CLASP2 interacts with a common motif found in several CLASP-binding proteins. This interaction drives the dynamic localization of CLASP2 to distinct cellular compartments, where CLASP2 accumulates in protein condensates at the cell cortex or the microtubule plus end. These condensates physically contact each other via CLASP2-mediated competitive binding, determining cortical microtubule targeting. The phosphorylation of CLASP2 modulates the dynamics of the condensate-condensate interaction and spatiotemporally navigates microtubule growth. Moreover, we identify additional CLASP-interacting proteins that are involved in condensate contacts in a CLASP2-dependent manner, uncovering a general mechanism governing microtubule targeting. Our findings not only unveil a tunable multiphase system regulating microtubule organization, but also offer general mechanistic insights into intricate protein-protein interactions at the mesoscale level.

CLASP-mediated competitive binding in protein condensates directs microtubule growth.,Jia X, Lin L, Guo S, Zhou L, Jin G, Dong J, Xiao J, Xie X, Li Y, He S, Wei Z, Yu C Nat Commun. 2024 Aug 2;15(1):6509. doi: 10.1038/s41467-024-50863-3. PMID:39095354[8]

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

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. ↑ 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
  3. ↑ Lansbergen G, Grigoriev I, Mimori-Kiyosue Y, Ohtsuka T, Higa S, Kitajima I, Demmers J, Galjart N, Houtsmuller AB, Grosveld F, Akhmanova A. CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta. Dev Cell. 2006 Jul;11(1):21-32. PMID:16824950 doi:http://dx.doi.org/S1534-5807(06)00252-8
  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. ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
  8. ↑ Jia X, Lin L, Guo S, Zhou L, Jin G, Dong J, Xiao J, Xie X, Li Y, He S, Wei Z, Yu C. CLASP-mediated competitive binding in protein condensates directs microtubule growth. Nat Commun. 2024 Aug 2;15(1):6509. PMID:39095354 doi:10.1038/s41467-024-50863-3

8whl, resolution 3.20Å

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