Limited mutations in full-length tetrameric human alpha2-macroglobulin abrogate binding of platelet-derived growth factor-BB and transforming growth factor-beta1.

The Journal of Biological Chemistry
Sanja ArandjelovicSteven L Gonias

Abstract

alpha2-Macroglobulin (alpha2M) inhibits diverse extracellular proteases, binds growth factors such as platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta1 (TGF-beta1), and carries beta-amyloid peptide. alpha2M may also trigger cell signaling by binding to the low density lipoprotein receptor-related protein (LRP-1) and/or other cell surface receptors. Based on studies with recombinant alpha2M fragments expressed in bacteria and synthetic peptides, we previously localized a growth factor-binding site near the center of the alpha2M subunit. However, because intact alpha2M forms a hollow cylinder structure, an alternative model for growth factor binding involves nonspecific entrapment within the alpha2M core. To distinguish between these two models, we engineered mutations in the putative growth factor binding sequence of full-length alpha2M. These mutations did not perturb the tetrameric structure of alpha2M, reaction with proteases, the thiol ester bonds, or binding to LRP-1. A single mutation (E730R) completely blocked binding of platelet-derived growth factor-BB to intact alpha2M. E730R did not alter TGF-beta1 binding; however, this mutation in combination with mutations at Glu714 and Asp719 elimina...Continue Reading

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Citations

May 24, 2008·The Journal of Biological Chemistry·Elisabetta MantuanoSteven L Gonias
Nov 7, 2009·Human Reproduction·Charles O A OmwandhoHans-Rudolf Tinneberg
Aug 5, 2008·Optometry and Vision Science : Official Publication of the American Academy of Optometry·Gordon W LaurieJason J Nichols
Jan 17, 2016·Biology of the Cell·Claudio Marcelo FaderMaría Isabel Colombo
Dec 14, 2018·Bioscience Reports·Ruben Adrian GrossoClaudio Marcelo Fader

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