Physical Chemistry Seminar: Dr. Samrat Mukhopadhyay, Indian Institute of Science Education and Research (IISER) Mohali

Physical Chemistry Seminar: Dr. Samrat Mukhopadhyay, Indian Institute of Science Education and Research (IISER) Mohali (Host: Dick Zare)

About the Talk

"A Deep Dive into Liquid-Liquid Phase Separation of Intrinsically Disordered Proteins"

Natively unfolded or intrinsically disordered proteins (IDPs) challenge the traditional sequence-structure-function paradigm and constitute one of the major classes of molecular workhorses in higher organisms. Unlike the (folded) globular proteins, IDPs lack the ability to undergo autonomous folding, exist as dynamic ensembles, and underscore the importance of conformational plasticity and heterogeneity in the protein function. However, disorder-to-function relationships are poorly understood. Additionally, the dysfunction of many IDPs is associated with a range of deadly diseases such as Alzheimer's and Parkinson's diseases and cancers. My laboratory has been investigating the structural and dynamical characteristics of a wide range of IDPs that are capable of transforming into highly ordered amyloid aggregates as well as highly dynamic liquid-like biomolecular condensates. I will describe our recent results that shed light into the unusual phase behavior of IDPs that undergo liquid-liquid phase separation leading to the formation of functional membrane-less organelles that can eventually undergo an aberrant liquid-to-solid phase transition into more ordered pathological aggregates. We demonstrated that an unusual cascade of intermolecular charge-transfer coupled with a relay of making-and-breaking of transient noncovalent interactions can govern liquid phase condensation of IDPs. Additionally, our intriguing observation suggested that the charge-transfer-mediated phase transition can modulate the mesoscale material property of these supramolecular condensates that can convert from a liquid-like state to a gel-like or a solid-like state. Our results provide a novel mechanistic underpinning that can have broad implications in a wide range of biomolecular condensates in physiology and disease.

References:

1.         "Intermolecular charge-transfer modulates liquid-liquid phase separation and liquid-to-solid maturation of an intrinsically disordered pH-responsive domain" P. Dogra, A. Joshi, A. Majumdar & S.  Mukhopadhyay.  J. Am. Chem. Soc. (in press).

              DOI: https://pubs.acs.org/doi/abs/10.1021/jacs.9b10892

2.         "Liquid-Liquid Phase Separation is Driven by Large-Scale Conformational Unwinding and Fluctuations of Intrinsically Disordered Protein Molecules" A. Majumdar, P. Dogra, S. Maity & S. Mukhopadhyay. J. Phys. Chem. Lett. 2019, 10, 3929-3936.

3.         "Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein" S. Arya, A. Singh, K. Bhasne, P. Dogra, A. Datta, P. Das & S. Mukhopadhyay. Biophys. J. 2018, 114, 2540-51.

4.         "Direct Observation of the Intrinsic Backbone Torsional Mobility of Disordered Proteins" N. Jain, D. Narang, K. Bhasne, V. Dalal, S. Arya, M. Bhattacharya & S. Mukhopadhyay. Biophys. J. 2016, 111, 768-774. 

About the Speaker

Research Area:

Intrinsically Disordered Proteins: Phase Transition, Misfolding, Aggregation, and Amyloid Formation.

Research Focus:

Proteins are the workhorses of the living systems. Traditionally, protein function was thought to depend on a unique well-defined 3D structure that is encoded by the amino acid sequence. However, current investigations have revealed that a large fraction of the proteome consists of polypeptide segments that lack a well-defined structure under physiological conditions. They belong to a distinct class of proteins termed as intrinsically disordered proteins (IDPs) that challenge the tenets of the traditional structure-function paradigm. The intrinsic disorder in the proteins allows the complex organisms to carry out multiple functions from the same proteins by adopting different conformational states. However, the disorder-to-function relationship is poorly understood. Additionally, dysfunction of many IDPs is associated with a range of deadly diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), frontotemporal dementias (FTDs) and cancers. The Mukhopadhyay lab utilizes a diverse range of approaches involving biophysics, biochemistry, chemical biology, cell and molecular biology, and advanced single-molecule and ultrafast spectroscopy to gain molecular insights into the conformational ensemble and dynamics, the protein hydration water, liquid-liquid phase separation, aggregation and amyloid formation from various IDPs containing low-complexity and prion-like domains. These studies are beginning to illuminate the unique molecular insights into the pivotal functional and pathological aspects of phase transition of IDPs.

Selected Publications

• "Liquid-Liquid Phase Separation is Driven by Large-Scale Conformational Unwinding and Fluctuations of Intrinsically Disordered Protein Molecules" A. Majumdar, P. Dogra, S. Maity & S. Mukhopadhyay* J. Phys. Chem. Lett. 2019, 10, 3929−3936.

• "Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein" S. Arya, A. Singh, K. Bhasne, P. Dogra, A. Datta,* P. Das,* & S. Mukhopadhyay* Biophys. J. 2018, 114, 2540–2551.

• "Synergistic Amyloid Switch Triggered by Early Heterotypic Oligomerization of Intrinsically Disordered α-Synuclein and Tau" K. Bhasne, S. Sebastian, N. Jain, & S. Mukhopadhyay* J. Mol. Biol. 2018, 430, 2508-2520.
• "Electrostatic lipid-protein interactions sequester the curli amyloid fold on the lipopolysaccharide membrane surface" H.M. Swasthi & S. Mukhopadhyay* J. Biol. Chem. 2017, 292, 19861-19872.

• "Direct Observation of the Intrinsic Backbone Torsional Mobility of Disordered Proteins" N. Jain, D. Narang, K. Bhasne, V. Dalal, S. Arya, M. Bhattacharya, & S. Mukhopadhyay* Biophys. J. 2016, 111, 768-774.
  
  For a complete list of publications: Click here