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Combinatorial protein–protein interactions on a polymerizing scaffold

Ortiz-Muñoz, Andrés and Medina-Abarca, Héctor F. and Fontana, Walter (2020) Combinatorial protein–protein interactions on a polymerizing scaffold. Proceedings of the National Academy of Sciences of the United States of America, 117 (6). pp. 2930-2937. ISSN 0027-8424. PMCID PMC7022191. doi:10.1073/pnas.1912745117.

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Scaffold proteins organize cellular processes by bringing signaling molecules into interaction, sometimes by forming large signalosomes. Several of these scaffolds are known to polymerize. Their assemblies should therefore not be understood as stoichiometric aggregates, but as combinatorial ensembles. We analyze the combinatorial interaction of ligands loaded on polymeric scaffolds, in both a continuum and discrete setting, and compare it with multivalent scaffolds with fixed number of binding sites. The quantity of interest is the abundance of ligand interaction possibilities—the catalytic potential Q—in a configurational mixture. Upon increasing scaffold abundance, scaffolding systems are known to first increase opportunities for ligand interaction and then to shut them down as ligands become isolated on distinct scaffolds. The polymerizing system stands out in that the dependency of Q on protomer concentration switches from being dominated by a first order to a second order term within a range determined by the polymerization affinity. This behavior boosts Q beyond that of any multivalent scaffold system. In addition, the subsequent drop-off is considerably mitigated in that Q decreases with half the power in protomer concentration than for any multivalent scaffold. We explain this behavior in terms of how the concentration profile of the polymer-length distribution adjusts to changes in protomer concentration and affinity. The discrete case turns out to be similar, but the behavior can be exaggerated at small protomer numbers because of a maximal polymer size, analogous to finite-size effects in bond percolation on a lattice.

Item Type:Article
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URLURL TypeDescription Information Paper CentralArticle
Ortiz-Muñoz, Andrés0000-0003-1824-3230
Medina-Abarca, Héctor F.0000-0001-5828-6492
Fontana, Walter0000-0003-4062-9957
Additional Information:© 2020 The Author(s). Published under the PNAS license. Edited by Peter Schuster, University of Vienna, Vienna, Austria, and approved December 24, 2019 (received for review July 24, 2019). Published January 24, 2020. We gratefully acknowledge discussions with Tom Kolokotrones, Eric Deeds, and Daniel Merkle. A.O.-M. and H.F.M.-A. contributed equally to this work. Author contributions: A.O.-M., H.F.M.-A., and W.F. designed research, performed research, contributed new reagents/analytic tools, and wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Subject Keywords:polymerizing scaffold | combinatorial assembly | pleiomorphic ensemble
Issue or Number:6
PubMed Central ID:PMC7022191
Record Number:CaltechAUTHORS:20200124-130052745
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Official Citation:Combinatorial protein–protein interactions on a polymerizing scaffold. Andrés Ortiz-Muñoz, Héctor F. Medina-Abarca, Walter Fontana. Proceedings of the National Academy of Sciences Feb 2020, 117 (6) 2930-2937; DOI: 10.1073/pnas.1912745117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100899
Deposited By: Tony Diaz
Deposited On:25 Jan 2020 03:28
Last Modified:16 Nov 2021 17:57

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