Temperature-Sensitive Contact Modes Allosterically Gate TRPV3

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2023-01-12
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Burns, Daniel
Potoyan, Davit A.
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bioRxiv
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Venditti, Vincenzo
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Chemistry

The Department of Chemistry seeks to provide students with a foundation in the fundamentals and application of chemical theories and processes of the lab. Thus prepared they me pursue careers as teachers, industry supervisors, or research chemists in a variety of domains (governmental, academic, etc).

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The Department of Chemistry was founded in 1880.

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1880-present

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Biochemistry, Biophysics and Molecular Biology

The Department of Biochemistry, Biophysics, and Molecular Biology was founded to give students an understanding of life principles through the understanding of chemical and physical principles. Among these principles are frontiers of biotechnology such as metabolic networking, the structure of hormones and proteins, genomics, and the like.

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The Department of Biochemistry and Biophysics was founded in 1959, and was administered by the College of Sciences and Humanities (later, College of Liberal Arts & Sciences). In 1979 it became co-administered by the Department of Agriculture (later, College of Agriculture and Life Sciences). In 1998 its name changed to the Department of Biochemistry, Biophysics, and Molecular Biology.

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1959–present

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  • Department of Biochemistry and Biophysics (1959–1998)

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Abstract
TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-em structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend, while others display non-linear and sometimes increasing contact-frequency trends. These modes describe the residue-level temperature response patterns that underlie the channel’s functional dynamics. With network analysis, we show that the community structure of the channel changes with temperature, providing a detailed description of temperature-dependent domain coupling. We also find a network of high centrality contacts that connects distant regions of the protomer to a point directly adjacent to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate’s state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer a model for thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis.
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This is a pre-print of the article Burns, Daniel, Vincenzo Venditti, and Davit A. Potoyan. "Temperature-Sensitive Contact Modes Allosterically Gate TRPV3." bioRxiv (2023): 2023-01. DOI: 10.1101/2023.01.02.522497. Copyright 2023 The Authors. Posted with permission.
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