BIFI TALK: Athi N Naganathan, Indian Institute of Technology Madras (IITM), Chennai, India

Title:  Conformational Tuning as a Mechanism to Determine Specificity and
Promiscuity

Abstract:

Paralogous proteins confer enhanced fitness to organisms via complex sequence-conformation codes that shape functional divergence, specialization, or promiscuity. Here, we resolve the underlying mechanism of promiscuous binding versus partial sub-functionalization by studying paralogous Acyl-CoA Binding Proteins (ACBPs) from Plasmodium falciparum. Combining experiments and simulations on two of the paralogs, A16 and A749, we show that minor sequence differences shape nearly every conformational feature. A749 displays a heterogeneous native ensemble, weaker thermodynamic coupling, enhanced fluctuations, and a larger binding-pocket volume, compared to A16. Tryptophan probes signal a graded reduction in the sampling of substates in the holo form, hinting at conformational-selection-like mechanism of binding. They exhibit a spectrum of binding affinities to acyl-CoAs with A749, the
more promiscuous and hence the likely ancestor, binding 1000-fold stronger to Lauroyl-CoA. We thus demonstrate how minor differences in long-range coupling and dynamics contribute to the evolution of contrasting functional repertoires in paralogs.

FRIDAY, 24th May 2024, 13:00 h
Edificio I+D (Aula room)