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New targets and designed inhibitors of ASAP Arf-GAPs derived from structural characterization of the ASAP1/440-kD ankyrin-B interaction.
Li, Yubing; Zhao, Yipeng; He, Yaojun; Liu, Fang; Xia, Lu; Liu, Kai; Zhang, Mingjie; Chen, Keyu.
Afiliación
  • Li Y; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518036, China; Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
  • Zhao Y; Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
  • He Y; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518036, China.
  • Liu F; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518036, China.
  • Xia L; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518036, China.
  • Liu K; Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
  • Zhang M; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518036, China; School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
  • Chen K; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518036, China. Electronic address: chenky@szbl.ac.cn.
J Biol Chem ; : 107762, 2024 Sep 10.
Article en En | MEDLINE | ID: mdl-39265663
ABSTRACT
ASAP1 and its paralog ASAP2 belong to a PI4,5P2-dependent Arf GTPase-activating protein (Arf-GAP) family capable of modulating membrane and cytoskeletal dynamics. ASAPs regulate cell adhesive structures such as invadosomes and focal adhesions during cell attachment and migration. Malfunctioning of ASAP1 has been implicated in the malignant phenotypes of various cancers. Here, we discovered that the SH3 domain of ASAP1 or ASAP2 specifically binds to a 12-residue, positively charged peptide fragment from the 440 kDa giant ankyrin-B, a neuronal axon specific scaffold protein. The high-resolution structure of the ASAP1-SH3 domain in complex with the gAnkB peptide revealed a non-canonical SH3-ligand binding mode with high affinity and specificity. Structural analysis of the complex readily uncovered a consensus ASAP1-SH3 binding motif, which allowed the discovery of a number of previously unknown binding partners of ASAP1-SH3 including Clasp1/Clasp2, ALS2, ß-Pix, DAPK3, PHIP, and Limk1. Fittingly, these newly identified ASAP1 binding partners are primarily key modulators of the cytoskeletons. Finally, we designed a cell-penetrating, highly potent ASAP1 SH3 domain binding peptide with a Kd ∼7 nM as a tool for studying the roles of ASAPs in different cellular processes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos