2. Academic Validation
  3. Insights into the distinct membrane targeting mechanisms of WDR91 family proteins

Insights into the distinct membrane targeting mechanisms of WDR91 family proteins

  • Structure. 2024 Dec 5;32(12):2287-2300.e4. doi: 10.1016/j.str.2024.09.023.
Xinli Ma 1,  Jian Li 1,  Nan Liu 2,  Surajit Banerjee 3,  Xiaotong Hu 1,  Xiaoyu Wang 1,  Jianshu Dong 4,  Kangdong Liu 5,  Chonglin Yang 2,  Zigang Dong 6
Affiliations

Affiliations

  • 1 China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450003, China.
  • 2 State Key Laboratory of Conservation and Utilization of Bio-Resources in Yunnan and Center for Life Science, School of Life Sciences, Yunnan University, Kunming 650091, China.
  • 3 Northeastern Collaborative Access Team, Argonne National Laboratory, Argonne, Illinois 60439, USA.
  • 4 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
  • 5 China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450003, China; College of Medicine, Zhengzhou University, Zhengzhou, Henan 450052, China.
  • 6 China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450003, China; College of Medicine, Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: dongzg@zzu.edu.cn.
PMID: 39426373 DOI: 10.1016/j.str.2024.09.023
Abstract

WDR91 and SORF1, members of the WD repeat-containing protein 91 family, control phosphoinositide conversion by inhibiting phosphatidylinositol 3-kinase activity on endosomes, which promotes endosome maturation. Here, we report the crystal structure of the human WDR91 WD40 domain complexed with Rab7 that has an unusual interface at the C-terminus of the Rab7 switch II region. WDR91 is highly selective for Rab7 among the tested GTPases. A LIS1 homology (LisH) motif within the WDR91 N-terminal domain (NTD) mediates self-association and may contribute partly to the augmented interaction between full-length WDR91 and Rab7. Both the Rab7 binding site and the LisH motif are indispensable for WDR91 function in endocytic trafficking. For the WDR91 orthologue SORF1 lacking the C-terminal WD40 domain, a C-terminal amphipathic helix (AH) mediates strong interactions with liposomes containing acidic lipids. During evolution the human WDR91 ancestor gene might have acquired a WD40 domain to replace the AH for endosomal membrane targeting.

Keywords

Rab7; SORF1; WD40 domain; WDR91; amphipathic helix; endocytosis; lisH motif; membrane binding; structure; switch region.

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