TIFR
Department of Chemical Sciences
School of Natural Sciences

August 3, 2017 at 4.00 pm in AG-80

Title :

The role of conformational dynamics in molecular recognition

Abstract :

Conformational dynamics plays a fundamental role in molecular recognition and activity in proteins. Ubiquitin and ubiquitin-like proteins are involved in nearly all aspects of cellular function. Nuclear magnetic resonance (NMR) spectroscopy and Molecular dynamics simulations were used to show that conformational selection underlies the allosteric interaction between ubiquitin conjugating enzyme (E2) and ubiquitin ligase (E3) [1]. The E2, Ube2g2 functions with the canonical E3, gp78 to assemble poly-ubiquitin chains on target substrates. Two domains of the gp78, RING and G2BR, bind to two distinct regions of Ube2g2, and activate it for ubiquitin (Ub) transfer. The conformational dynamics in Ube2g2 reveals a clear correlation of binding G2BR and RING with sequential progression towards Ub transfer. The interrelationship of the existence and exchange between ground and excited states leads to a dynamic energy landscape model, in which the redistribution of populations contributes to allostery and activation [1]. Briefly, our current results about conformational selection of Ubiquitin will be discussed. Subsequently, I will discuss systems where the functional implications of conformational selection mechanism will be explored. The divergent evolution of proteins has been hypothesized to rely on the conformational selection mechanism [2]. The Small Ubiquitin-like Modifier (SUMO) protein can be investigated as a model system to test the hypothesis that conformational selection is a relic of evolution in ubiquitin-like protein family [2]. The conformational selection in a transporter protein partitioning between aqueous and lipid phases remains unexplored. I will discuss the selection of different conformations of the Synaptotagmin-like mitochondrial-lipid binding proteins (SMP) domain of the transporter protein Extended synaptotagmin (Esyt) [3] based on the physico-chemical properties (e.g., hydrophobicity) by different phases (aqueous, lipid) existing within the neuron, which is involved in transfer of lipid molecules from endoplasmic reticulum to plasma membrane in the axons [4]. The mechanism of Esyt has importance in understanding the axon degeneration in genetic diseases hereditary spastic paraplegia (HSP) [5] and amyotrophic lateral sclerosis (ALS) [6].

 

Reference:

 

1.Chakrabarti et al. (2017) Structure 25 794-805.

2.Khersonsky & Tawfik (2010) Annu Rev Biochem. 79 471-505.

3.Schauder et al. (2014) Nature 510 552-555.

4.Min et al. (2007) PNAS (USA) 104 3823-3828.

5.Blackstone (2012) Annu Rev Neurosci. 35 25-47.

6.Teuling et al. (2007) J. Neurosci. 27 9801-9815.