Mutations at the dimer interface and surface residues of Nm23-H1 metastasis suppressor affect its expression and functio
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Mutations at the dimer interface and surface residues of Nm23‑H1 metastasis suppressor affect its expression and function Yuanjun Li1,3 · Wen Liu1 · Vasu Saini1 · Yung H. Wong1,2 Received: 29 April 2020 / Accepted: 11 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The Nm23 metastasis suppressor family is involved in a variety of physiological and pathological processes including cell proliferation, differentiation, tumorigenesis, and metastasis. Given that Nm23 proteins may function as hexamers composed of different members of the family, especially Nm23-H1 and H2 isoforms, it is pertinent to assess the importance of interface and surface residues in defining the functional characteristics of Nm23 proteins. Using molecular modeling to identify clusters of residues that may affect dimer formation and isoform specificity, mutants of Nm23-H1 were constructed and assayed for ys39 affected the expression level their ability to modulate cell migration. Mutations of dimer interface residues Gly22 and L of Nm23-H1, without altering the transcript level. The reduced protein expression was not due to increased protein degradation or altered subcellular distribution. Substitution of the surface residues of Nm23-H1 with Nm23-H2-specific S er131 and/ 124/135 or Lys affected the electrophoretic mobility of the protein. Moreover, in cell migration assays, several mutants with altered surface residues exhibited impaired ability to suppress the mobility of MDA-MB-231 cells. Collectively, the study suggests that disrupting the dimer interface may affect the expression of Nm23-H1, while the residues at α-helix and β-sheet on the surface of Nm23-H1 may contribute to its metastasis suppressive function. Keywords Nm23-H1 · Metastasis suppressor · Hexamer · Structure
Introduction Nm23, also called non-metastatic 23 or NME, was the first identified metastasis suppressor with the ability to inhibit metastasis formation [1, 2]. Over the past two decades, numerous studies ranging from transfection to knockout mice experiments have convincingly demonstrated the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11010-020-03836-1) contains supplementary material, which is available to authorized users. * Yung H. Wong [email protected] 1
Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
2
State Key Laboratory of Molecular Neuroscience and the Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, China
3
Present Address: Eye Center of Xiangya Hospital, Hunan Key Laboratory of Opthalmology, Xiangya Hospital, Central South University, Changsha, China
multifunctional and metastasis suppressive effect of Nm23. Comprising ten gene members, the human Nm23 gene family is involved in diverse physiological and pathological processes including proliferation, differentiation, development, ciliary functions, and metastasis [3, 4]. Nm
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