Protein-protein recognition between acyltransferases and acyl carrier proteins in multimodular polyketide synthases.

Biochemistry
Fong T WongChaitan Khosla

Abstract

Acyltransferase (AT) domains of multimodular polyketide synthases are the primary gatekeepers for stepwise incorporation of building blocks into a growing polyketide chain. Each AT domain has two substrates, an alpha-carboxylated CoA thioester (e.g., malonyl-CoA or methylmalonyl-CoA) and an acyl carrier protein (ACP). Whereas the acyl-CoA specificity of AT domains has been extensively investigated, little is known about their ACP specificity. Guided by recent high-resolution structural insights, we have systematically probed the protein-protein interactions between AT domains, ACP domains, and the linkers that flank AT domains. Representative AT domains of the 6-deoxyerythronolide B synthase (DEBS) have greater than 10-fold specificity for their cognate ACP substrates as compared to other ACP domains from the same synthase. Both of the flanking (N- and C-terminal) linkers of an AT domain contributed to the efficiency and specificity of transacylation. As a frame of reference, the activity and specificity of a stand-alone AT domain from the "AT-less" disorazole synthase (DSZS) were also quantified. The activity (k(cat)/K(M)) of this AT was >250-fold higher than the corresponding values for DEBS AT domains. Although the AT from D...Continue Reading

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Citations

Dec 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·Shiven KapurChaitan Khosla
Jul 19, 2012·Journal of Biomolecular Structure & Dynamics·Gitanjali YadavDebasisa Mohanty
May 31, 2013·Journal of the Royal Society, Interface·Briana J Dunn, Chaitan Khosla
Jun 27, 2014·Nature·Jonathan R WhicherGeorgios Skiniotis
Feb 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Akimasa MiyanagaTadashi Eguchi
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Jul 6, 2013·Chembiochem : a European Journal of Chemical Biology·Ewa Maria MusiolTilmann Weber
Jul 15, 2015·Journal of the American Chemical Society·Jaclyn M WinterYi Tang
Dec 20, 2012·Critical Reviews in Biochemistry and Molecular Biology·Wei XuYi Tang
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Nov 26, 2020·ACS Chemical Biology·Anna D GrabowskaLionel Mourey
Sep 3, 2021·Acta Crystallographica. Section F, Structural Biology Communications·Akimasa MiyanagaTadashi Eguchi

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