chi2008

Notes:

• Chi’s paper said “Our results reveal that the sparse energetic network in PSD95 PDZ3 is not affecting ligand binding more than non-network residues. The observed coupling energies for binding can be explained by a model where distance is correlated with coupling (8), as shown previously for the barnase–barstar complex (15) and Staphylococcal nuclease (8, 16). Thus, statistical coupling inferred from multiple sequence alignment is not necessarily a true reporter of functional coupling.”

• In my opinion, these are two issues. Coevolved network of residues in PSD95-PDZ3 domain effects the energy propagation after peptide binding to PDZ. It doesn’t matter whether it determines the binding interaction or not.  (Am I wrong??)

• A valuable information is “previous work on PSD95 PDZ3 in our laboratory suggested that this PDZ domain is conformationally rigid upon ligand binding in agreement with the crystal structure”.

Chi CN, Elfstrom L, Shi Y, Snall T, Engstrom A, et al. (2008) Reassessing a sparse energetic network within a single protein domain. Proc Natl Acad Sci U S A 105: 4679-4684.

Reassessing a sparse energetic network within a single protein domain

Lockless and Ranganathan (7) set out to investigate whether allostery could be predicted from sequence conservation. They found a coevolved network of residues in the PDZ domain family of proteins, and these statistically coupled residues were confirmed by experiments on PSD95 PDZ3 to be energetically coupled (7). This study has served as a classic example of allostery in a single protein domain, with a ‘‘sparse network’’ of energetically linked positions that could affect function, in this case ligand binding. However, pathways of energetic connectivity inferred from statistical analysis have been questioned because the correlated mutation algorithm that was used finds pairs of residues that are close in physical space in the protein structure and it is therefore not surprising that the residues actually do couple (8). Furthermore, other issues regarding the validity of the statistical method used by Lockless and Ranganathan have been raised: the algorithm used is not symmetric (9), does not incorporate evolutionary noise (10), and performs less well than other algorithms (8, 9, 11). From an experimental point of view, previous work on PSD95 PDZ3 in our laboratory suggested that this PDZ domain is conformationally rigid upon ligand binding (12) in agreement with the crystal structure (13). Finally, for PTP-BL PDZ2 the energetic coupling between two of the network residues was found to be absent (14). In light of these uncertainties, we here reassess the network of residues proposed to form a pathway of energetic connectivity in PDZ domains. Our results reveal that the sparse energetic network in PSD95 PDZ3 is not affecting ligand binding more than non-network residues. The observed coupling energies for binding can be explained by a model where distance is correlated with coupling (8), as shown previously for the barnase–barstar complex (15) and Staphylococcal nuclease (8, 16). Thus, statistical coupling inferred from multiple sequence alignment is not necessarily a true reporter of functional coupling.

Lockless SW, Ranganathan R (1999) Evolutionarily conserved pathways of energetic connectivity in protein families. Science 286: 295-299.

Evolutionarily conserved pathways of energetic connectivity in protein families

Abstract: For mapping energetic interactions in proteins, a technique was developed that uses evolutionary data for a protein family to measure statistical interactions between amino acid positions. For the PDZ domain family, this analysis predicted a set of energetically coupled positions for a binding site residue that includes unexpected long-range interactions. Mutational studies conÞrm these predictions, demonstrating that the statistical energy function is a good indicator of thermodynamic coupling in proteins. Sets of interacting residues form connected pathways through the protein fold that may be the basis for efÞcient energy conduction within proteins.

Conclusion: The ability to efficiently propagate energy through tertiary structure is a fundamental property of many proteins and is the physical basis for key biological properties such as allostery and signal transmission. The coupled pathways may represent conduits along which energy distributes through a protein structure to generate these functional features. Protein interaction modules such as the PDZ and POZ domains are known to play key roles as organizing centers for multiprotein signaling complexes in which proteins are assembled into functional macromolecular units (27). In addition to this established role in cellular scaffolding, the finding of energetically coupled pathways within these domains raises the possibility that the interaction modules may also act as conductors of signaling. In the PDZ domain, evidence forsuch a role comes from the finding that interaction of the guanylate kinase domain of the multi-PDZ protein PSD-95 with MAP1A depends on the binding of target peptides to the PSD-95 PDZ domains (28).

As with any thermodynamic mapping, the approach described here can identify couplings, but it does not itself reveal the physical mechanism of the energetic coupling. Nevertheless, the arrangement of coupled residues into ordered pathways through the core of the PDZ and POZ protein folds suggests that one mechanism may be simple mechanical deformation of the structure along coupled pathways. Given the evolutionary basis of the statistical analysis, we infer that these pathways of energetic connectivity have emerged early in the evolution of the protein folds and, much like the atomic structure, are fundamentally conserved features of the domain families. With growing sequence data for evolutionarily distant genomes, the mapping of energetic connectivity for many fold families should be a realistic goal.