Mapping the allosteric network within a SH3 domain

Malagrinò, Francesca; Troilo, Francesca; Bonetti, Daniela; Toto, Angelo; Gianni, Stefano

doi:10.1038/s41598-019-44656-8

Cited by 21 publications

(21 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the mainly positive ΔΔΔG c values for PDZ3, surprisingly, we observe primarily negative ΔΔΔG c values for the allosteric network in PSG probed by CRIPT P-3 6 AA, suggesting a nonoptimized system. A tendency for negative ΔΔΔG c values was recently reported for an SH3 domain (34). Thus, the presence of allosteric networks may not necessarily be linked with binding selectivity but may also trace the communication pathways between energetically interacting domains in supramodules.…”

Section: Discussionmentioning

confidence: 80%

See 1 more Smart Citation

Supertertiary protein structure affects an allosteric network

Laursen

Kliche

Gianni

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The notion that protein function is allosterically regulated by structural or dynamic changes in proteins has been extensively investigated in several protein domains in isolation. In particular, PDZ domains have represented a paradigm for these studies, despite providing conflicting results. Furthermore, it is still unknown how the association between protein domains in supramodules, consitituting so-called supertertiary structures, affects allosteric networks. Here, we experimentally mapped the allosteric network in a PDZ:ligand complex, both in isolation and in the context of a supramodular structure, and show that allosteric networks in a PDZ domain are highly dependent on the supertertiary structure in which they are present. This striking sensitivity of allosteric networks to the presence of adjacent protein domains is likely a common property of supertertiary structures in proteins. Our findings have general implications for prediction of allosteric networks from primary and tertiary structures and for quantitative descriptions of allostery.

show abstract

Section: Discussionmentioning

confidence: 80%

“…The pattern was observed in both PDZ3 and PSG. Interestingly, the two networks contain both positive and negative coupling free energies, which could arise from lost selectivity and broader binding profile (34). Therefore, the allosteric networks in PDZ3 and PSG upon binding of CRIPT 15 AA appear more similar (Figs.…”

Section: Resultsmentioning

confidence: 99%

Supertertiary protein structure affects an allosteric network

Laursen

Kliche

Gianni

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast to the mainly positive DDDGc values for PDZ3, surprisingly, we observe primarily negative DDDGc values for the allosteric network in PSG probed by CRIPTP-3 6 AA, suggesting a non-optimized system. A tendency for negative DDDGc values were recently reported for an SH3 domain (34). Thus, the presence of allosteric networks may not necessarily be linked with binding selectivity but may also trace the communication pathways between energetically interacting domains in supramodules.…”

Section: The Significance Of Positive D Dd Dd Dg C Values For Allostementioning

confidence: 84%

“…The pattern was observed in both PDZ3 and PSG. Interestingly, the two networks contain both positive and negative coupling free energies, which could arise from lost selectivity and broader binding profile (34). Therefore the allosteric networks in PDZ3 and PSG upon binding of CRIPT 15 AA appear more similar ( Figure 2C and F and 3).…”

Section: The Allosteric Network In Pdz3 and Psg Are Perturbed By Lonmentioning

confidence: 98%

Supertertiary protein structure affects an allosteric network

Laursen

Kliche

Gianni

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Corresponding authors: Stefano.Gianni@uniroma1.it; Per.Jemth@imbim.uu.seThe notion that protein function is allosterically regulated by structural or dynamic changes in proteins has been extensively investigated in several protein domains in isolation. In particular, PDZ domains have represented a paradigm for these studies, despite providing conflicting results. Furthermore, it is still unknown how the association between protein domains in supramodules, consitituting so-called supertertiary structure, affects allosteric networks. Here, we experimentally mapped the allosteric network in a PDZ:ligand complex, both in isolation and in the context of a supramodular structure, and show that allosteric networks in a PDZ domain are highly dependent on the supertertiary structure in which they are present. This striking sensitivity of allosteric networks to presence of adjacent protein domains is likely a common property of supertertiary structures in proteins.Our findings have general implications for prediction of allosteric networks from primary and tertiary structure and for quantitative descriptions of allostery. Abstract IntroductionAllosteric regulation is an essential function of many proteins, well established in multimeric proteins with well-defined conformational changes. From a biological perspective, such allostery plays important roles, for example in regulation of enzyme activity and binding of oxygen to hemoglobin, which was the basis for models such as MWC (1) and KNF (2). More recently the concept has been extended to monomeric proteins (3) and intrinsically disordered proteins (4, 5). Here, allostery is a process, where a signal propagates from one site to a physically distinct site, although the exact mechanism is elusive (6). Thus, as experimental approaches have developed the definition of the allosteric mechanism has evolved too and it is now spanning from the classical structure based allostery to the ensemble nature of allostery, and provides the framework for capturing allostery from rigid and structured proteins to dynamic and disordered proteins (7).PDZ3 from PSD-95 has been extensively used as a model system for allostery in a single protein domain. Originally, it was used as a benchmark of a statistical method to predict allostery from co-variation of mutations (8) and has since then been subject to study by numerous methods (9). PDZ domains are small protein domains, around 100 amino acid residues, with a specific fold that contains 5-6 b strands and 2-3 a-helices ( Figure 1C). The PDZ domain family is one of the most abundant protein-protein interaction domains in humans and it is often found in scaffolding or signalling proteins. PDZ domains bind to short interaction motifs (3-6 residues), usually at the C-terminus of ligand proteins. Looking at PDZ3 as a system to understand principles that underlie allosteric regulation reveals the complexity of the phenomenon. The first allosteric network in PDZ3 was determined by statistical coupling analysis and depicted a network that propagates f...

show abstract

“…Moreover, in this model, these changes in protein domain composition were manifested at an organism level. Thus, SH3 was observed as a highly abundant protein domain in translocations, which binds ligands (25, 26) and mediates PPIs (34). Notably, the repetitive domains, such as Ank (21-23) and WD40 (24) appeared in many copies in proteins.…”

Section: Discussionmentioning

confidence: 99%

EvoProDom: Evolutionary model of protein families by means of translocations of protein domains

Carmi

Gorohovski

Frenkel‐Morgenstern

2020

Preprint

View full text Add to dashboard Cite

† These authors contributed equally to this work. AbstractHere, we developed a novel evolution of protein domains (EvoProDom) model for evolution of proteins, which was based on mix and merge of protein domains. We collected and integrated genomic and proteome data for 109 organisms. These data include protein domain content and orthologous protein families. In EvoProDom, we defined evolutionary events, such as translocations, as reciprocal exchanges of protein domains between orthologous proteins of different organisms. We found that protein domains, which frequently appear in translocation events, were enriched in trans-splicing events, i.e., producing novel transcripts fused from two distinct genes. We presented in EvoProDom, a general method to obtain protein domain content and orthologous protein annotation, by predicting these data from protein sequences using the Pfam search tool and KoFamKOALA, respectively. This method can be implemented in other research such as proteomics, protein design and host-virus interactions.We hypothesized that proteins evolve by means of "mix and merge" or "shuffling" of 113 protein domains, which are distinct functional units (1, 20). The evolutionary model that 114 7 described protein evolution by means of protein domain dynamics was termed 115EvoProDom. The EvoProDom model defined and formulated standard evolutionary 116 mechanisms such as translocations, duplications and indel (insertion and deletion) events, 117 which acted on protein domains that were realized as Pfam domains (6, 7). Therefore, 118proteins, under the EvoProDom model, gained or lost their function based on the 119 presence or absence of respective function-conferring domains. Accordingly, proteins 120 were modeled as sets of protein domains; and evolutionary events, such as translocations, 121 were defined. These describe the gain and loss of particular domains between domain sets 122 or DAs. The KEGG database catalogs diverse taxa and forms groups of orthologous 123 proteins (KO) based on shared function. Thus, all members of the KO group were 124 orthologous proteins (8, 12, 13). Additionally, in the EvoProDom model, proteins were 125 assigned to KO groups (see Materials and Methods). Consequently, translocation events 126 were mapped to groups of organisms according to underlying changes in DA. Thus, 127 evolutionary events, which acted upon domains and manifested as changes in DA were 128 reflected at the organism level. A link between changes at these two levels was therefore 129 established. The EvoProDom model was implemented with and tested on EvoProDomDB 130 (see Materials and Methods). In total, 5,548 translocation events, involving 94 protein 131 super families, excluding an "unknown" super family, were found ( Table 2). This result 132 indicates the existence of multiple evolutionary translocation events as defined by the 133 model. 134Mapping of genes to proteins and alternative splicing 135 EvoProDom combined genomic information (genes) with proteins, and in turn, proteins 136 with Pfam doma...

show abstract

Mapping the allosteric network within a SH3 domain

Cited by 21 publications

References 32 publications

Supertertiary protein structure affects an allosteric network

Supertertiary protein structure affects an allosteric network

Supertertiary protein structure affects an allosteric network

EvoProDom: Evolutionary model of protein families by means of translocations of protein domains

Contact Info

Product

Resources

About