The PDZ Domain as a Complex Adaptive System

Alexei Kurakin,Dale E Bredesen,Andrzej Swistowski,Susan C Wu,Wenqing Xu

doi:10.1371/journal.pone.0000953

Alexei Kurakin, Dale E Bredesen + Show 3 more

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https://doi.org/10.1371/journal.pone.0000953

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Journal: PloS one	Publication Date: Sep 26, 2007
Citations: 62	License type: CC BY 4.0

Affiliation: Buck Institute for Research on Aging

Abstract

Specific protein associations define the wiring of protein interaction networks and thus control the organization and functioning of the cell as a whole. Peptide recognition by PDZ and other protein interaction domains represents one of the best-studied classes of specific protein associations. However, a mechanistic understanding of the relationship between selectivity and promiscuity commonly observed in the interactions mediated by peptide recognition modules as well as its functional meaning remain elusive. To address these questions in a comprehensive manner, two large populations of artificial and natural peptide ligands of six archetypal PDZ domains from the synaptic proteins PSD95 and SAP97 were generated by target-assisted iterative screening (TAIS) of combinatorial peptide libraries and by synthesis of proteomic fragments, correspondingly. A comparative statistical analysis of affinity-ranked artificial and natural ligands yielded a comprehensive picture of known and novel PDZ ligand specificity determinants, revealing a hitherto unappreciated combination of specificity and adaptive plasticity inherent to PDZ domain recognition. We propose a reconceptualization of the PDZ domain in terms of a complex adaptive system representing a flexible compromise between the rigid order of exquisite specificity and the chaos of unselective promiscuity, which has evolved to mediate two mutually contradictory properties required of such higher order sub-cellular organizations as synapses, cell junctions, and others – organizational structure and organizational plasticity/adaptability. The generalization of this reconceptualization in regard to other protein interaction modules and specific protein associations is consistent with the image of the cell as a complex adaptive macromolecular system as opposed to clockwork.

Highlights

Protein interaction modules, such as PDZ, SH3, WW, EH, SH2 and other domains, mediate protein-protein interactions by recognizing and binding short and usually linear peptide epitopes within their interacting partners [1,2,3,4]
In order to gain insight into the pattern recognition differences of the PDZ domains that belong to the same class but are able to differentiate between peptide ligands sharing the class-defining Cterminal consensus, we investigated a particular case of this general puzzle, namely, the differences in recognition preferences between the second and third PDZ domains of post-synaptic density 95 (PSD95), which are classified as type I PDZ domains but are known to discriminate between various X-(S/T)-X-(V/I/L)-COOH ligands [17,18]
Summarizing the recognition patterns of the PSD95 and SAP97 PDZ domains inferred from the comparative analysis of amino acid organization of their affinity-ranked artificial and natural ligands, the PSD95 and SAP97 PDZ domains prefer positively charged residues, lysine and arginine, in the positional window ‘‘24 to 27’’, while strongly favoring lysine or arginine at the position ‘‘24’’, glutamate at the position ‘‘23’’, threonine at the position ‘‘22’’ and valine at the position ‘‘0’’

Summary

Introduction

Protein interaction modules, such as PDZ, SH3, WW, EH, SH2 and other domains, mediate protein-protein interactions by recognizing and binding short and usually linear peptide epitopes within their interacting partners [1,2,3,4]. 90 amino acids long, PDZ domain was first discovered as sequence repeats in the primary structures of the post-synaptic density 95 (PSD95), disklarge (Dlg) and zona occludens-1 (ZO-1) proteins [6]. Later it was identified in many other proteins and the first draft of the human genome ranked the PDZ domain family as number 19 among the most abundant domain families [7]. The abundance of PDZ domains in metazoan genomes together with the scarcity of canonical PDZ domains in non-metazoans indicates a possibly critical function of PDZ domains in multicellular organization [8]

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