TY - JOUR

T1 - On the specificity of protein-protein interactions in the context of disorder

AU - Teilum, Kaare

AU - Olsen, Johan G.

AU - Kragelund, Birthe B.

PY - 2021

Y1 - 2021

N2 - With the increased focus on intrinsically disordered proteins (IDPs) and their large interac-tomes, the question about their specificity - or more so on their multispecificity - arise. Here we recapitulate how specificity and multispecificity are quantified and address through examples if IDPs in this respect differ from globular proteins. The conclusion is that quantitatively, globular proteins and IDPs are similar when it comes to specificity. However, compared with globular proteins, IDPs have larger interactome sizes, a phe-nomenon that is further enabled by their flexibility, repetitive binding motifs and propen-sity to adapt to different binding partners. For IDPs, this adaptability, interactome size and a higher degree of multivalency opens for new interaction mechanisms such as facili-tated exchange through trimer formation and ultra-sensitivity via threshold effects and ensemble redistribution. IDPs and their interactions, thus, do not compromise the defin-ition of specificity. Instead, it is the sheer size of their interactomes that complicates its calculation. More importantly, it is this size that challenges how we conceptually envision, interpret and speak about their specificity.

AB - With the increased focus on intrinsically disordered proteins (IDPs) and their large interac-tomes, the question about their specificity - or more so on their multispecificity - arise. Here we recapitulate how specificity and multispecificity are quantified and address through examples if IDPs in this respect differ from globular proteins. The conclusion is that quantitatively, globular proteins and IDPs are similar when it comes to specificity. However, compared with globular proteins, IDPs have larger interactome sizes, a phe-nomenon that is further enabled by their flexibility, repetitive binding motifs and propen-sity to adapt to different binding partners. For IDPs, this adaptability, interactome size and a higher degree of multivalency opens for new interaction mechanisms such as facili-tated exchange through trimer formation and ultra-sensitivity via threshold effects and ensemble redistribution. IDPs and their interactions, thus, do not compromise the defin-ition of specificity. Instead, it is the sheer size of their interactomes that complicates its calculation. More importantly, it is this size that challenges how we conceptually envision, interpret and speak about their specificity.

KW - PROTEIN-PROTEIN INTERACTION

KW - TRANSACTIVATION DOMAIN INTERACTION

KW - NATIVELY UNFOLDED PROTEINS

KW - LIQUID-PHASE-SEPARATION

KW - SHORT LINEAR MOTIF

KW - INTRINSIC DISORDER

KW - BINDING-AFFINITY

KW - PCNA-BINDING

KW - PIP BOX

KW - P53

U2 - 10.1042/BCJ20200828

DO - 10.1042/BCJ20200828

M3 - Review

C2 - 34101805

VL - 478

SP - 2035

EP - 2050

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 11

ER -