Origins of Allostery and Evolvability in Proteins: A Case Study

Abstract

Proteins display the capacity for adaptation to new functions, a property critical for evolvability. But what structural principles underlie the capacity for adaptation? Here, we show that adaptation to a physiologically distinct class of ligand specificity in a PSD95, DLG1, ZO-1 (PDZ) domain preferentially occurs through class-bridging intermediate mutations located distant from the ligand-binding site. These mutations provide a functional link between ligand classes and demonstrate the principle of "conditional neutrality" in mediating evolutionary adaptation. Structures show that class-bridging mutations work allosterically to open up conformational plasticity at the active site, permitting novel functions while retaining existing function. More generally, the class-bridging phenotype arises from mutations in an evolutionarily conserved network of coevolving amino acids in the PDZ family (the sector) that connects the active site to distant surface sites. These findings introduce the concept that allostery in proteins could have its origins not in protein function but in the capacity to adapt.

Distinct Roles for Conformational Dynamics in Protein-Ligand Interactions

“…This notion is supported by our previous analysis of sequence conservation of Tiam-family PDZ domains that showed the identity of the four residues in the QM segregate into four distinct Tiam subfamilies with Tiam1 and Tiam2 at the extremes (Shepherd et al, 2011). The onset of large-scale evolutionary datasets (Aakre et al, 2015; Raman et al, 2016) should provide new and interesting opportunities to probe the role of conformational dynamics in molecular evolution.…”

Site‐Resolved Observation of Vibrational Energy Transfer Using a Genetically Encoded Ultrafast Heater

“…[3,[28][29][30][31] Statistical coupling analysis of evolutionary conserved residues [28] and molecular dynamics simulations [3,30] indicate pathways of energetic connectivity in this highly abundant protein interaction domain. Ford emonstration, we chose the third PDZ domain from the neuronal post-synaptic density-95 protein (PSD-95-PDZ3, herein referred to as PDZ), which has served as am odel system for the study of allostery in single-domain proteins with various approaches.…”

“…Ford emonstration, we chose the third PDZ domain from the neuronal post-synaptic density-95 protein (PSD-95-PDZ3, herein referred to as PDZ), which has served as am odel system for the study of allostery in single-domain proteins with various approaches. [3,[28][29][30][31] Statistical coupling analysis of evolutionary conserved residues [28] and molecular dynamics simulations [3,30] indicate pathways of energetic connectivity in this highly abundant protein interaction domain. [32] Available crystal structures with bound peptide substrate [29,33] guided the selection of the AzAla VET donor placement sites.F or the first VET experiments of this kind, we selected two mutation sites,o ne located in the protein interior (F325;F igure 2c)a nd one at the surface (F340;F igure 2e), both being not too distant from the VET sensor Aha (see below), which was positioned in am odified peptide ligand bound to the peptide binding site of PDZ.…”

A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases

“…A recent investigation of the evolution of ligand specificity in PDZ domains proposed that allostery produces conformational flexibility and thus may arise as a consequence of evolutionary history (Raman et al, 2016). Here we propose a mechanism whereby pre-existing allosteric regulatory modules such as we have identified for PP2C phosphatases facilitated the evolution of new enzymatic activities by transition through a pseudoenzyme intermediate that is pre-programmed for regulation.…”