Molecular mechanisms of gating and selectivity in transport channels

Gamini, Ramya Bhargavi

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https://hdl.handle.net/2142/45293 Copy

Description

Title

Molecular mechanisms of gating and selectivity in transport channels

Author(s)

Gamini, Ramya Bhargavi

Issue Date

2013-08-22T16:35:05Z

Director of Research (if dissertation) or Advisor (if thesis)

Schulten, Klaus J.

Doctoral Committee Chair(s)

Schulten, Klaus J.

Committee Member(s)

• Tajkhorshid, Emad
• Grosman, Claudio F.

Department of Study

School of Molecular & Cell Bio

Discipline

Biophysics & Computnl Biology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Transport Channels
• Molecular Dynamics
• nuclear pore complex
• mechanosensitive channel of small conductance

Abstract

Transport channels and pores are of fundamental importance for translocation of molecules across the otherwise-impermeable biological membrane. As a conduit for the passage of material, specific membrane channels must accomplish the task of selective transport of molecules, while preventing unnecessary loss of other cellular material. The nuclear pore complex (NPC), and the mechanosensitive channel of small conductance, MscS are the focus of the research presented in this thesis. NPCs are sole gateways for passage of material across the nuclear envelope of eukaryotic cells. Several unstructured proteins that are rich in phenylaline- glycine motifs (FG-nups) form the central transport channel. Small molecules passively diffuse through the channel but, larger molecules are selectively transported via transport factors (TFs), which apparently interact with the FG-repeats of the nups in the channel. To understand how nups are assembled in the interior of the NPC, assemblies of one kind of nup, starting from different initial states, are investigated. Results suggest nups form different structures in different regions of the central channel. While only molecules of size < 9nm can penetrate through, a limit known for passive diffusion, the resulting structure posed a selectivity barrier for larger molecules that can be penetrated only via TF interactions. Mechanosensitive (MS) channels, bacterial inner-membrane proteins, open and close in response to mechanical stimuli such as changes in membrane tension during osmotic stress. These channels act as safety valves preventing cell lysis upon hypoosmotic cell swelling: the channels open under membrane tension to release osmolytes along with water. MscS, consists, beside the transmembrane channel, of a large cytoplasmic domain (CD) that features a balloon-like, water filled chamber opening to the cytoplasm through seven side pores and a small distal pore. The CD is apparently a molecular sieve covering the channel, that optimizes loss of osmolytes during osmoadaptation. Diffusion theory and MD simulations are employed to explore the transport kinetics of Glu- and K+ as representative osmolytes. A role of a filter is suggested for the CD such that it balances passage of Glu- and K+ osmolytes, to yield a largely neutral efflux, thereby, reducing cell depolarization in the open state that also conserves to a large degree the essential metabolite Glu-.

Graduation Semester

2013-08

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http://hdl.handle.net/2142/45293

Copyright and License Information

Copyright 2013 Ramya Bhargavi Gamini

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