Structural analysis of the KRIT1 ankyrin repeat and FERM domains reveals a conformationally stable ARD-FERM interface

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• 作者：Rong Zhang^a ; Xiaofeng Li^a ; Titus J. Boggon^a ; ^b ; ^{titus.boggon@yale.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Crystal structure ; X-ray crystallography ; Ankyrin repeat ; Protein complex ; Cerebral cavernous malformations
• 刊名：Journal of Structural Biology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：192
• 期：3
• 页码：449-456
• 全文大小：2804 K

文摘

Cerebral cavernous malformations (CCM) are vascular dysplasias that usually occur in the brain and are associated with mutations in the KRIT1/CCM1, CCM2/MGC4607/OSM/Malcavernin, and PDCD10/CCM3/TFAR15 genes. Here we report the 2.9 Å crystal structure of the ankyrin repeat domain (ARD) and FERM domain of the protein product of KRIT1 (KRIT1; Krev interaction trapped 1). The crystal structure reveals that the KRIT1 ARD contains 4 ankyrin repeats. There is an unusual conformation in the ANK4 repeat that is stabilized by Trp-404, and the structure reveals a solvent exposed ankyrin groove. Domain orientations of the three copies within the asymmetric unit suggest a stable interaction between KRIT1 ARD and FERM domains, indicating a globular ARD–FERM module. This resembles the additional F0 domain found N-terminal to the FERM domain of talin. Structural analysis of KRIT1 ARD–FERM highlights surface regions of high evolutionary conservation, and suggests potential sites that could mediate interaction with binding partners. The structure therefore provides a better understanding of KRIT1 at the molecular level.