Structure and Function of the Bestrophin family of calcium-activated chloride channels

ABSTRACT

Bestrophins are a family of calcium-activated chloride channels (CaCCs) with relevance to human physiology and a myriad of eye diseases termed “bestrophinopathies”. Since the identification of bestrophins as CaCCs nearly two decades ago, extensive studies from electrophysiological and structural biology perspectives have sought to define their key channel features including calcium sensing, gating, inactivation, and anion selectivity. The initial X-ray crystallography studies on the prokaryotic homolog of Best1, Klebsiella pneumoniae (KpBest), and the Best1 homolog from Gallus gallus (chicken Best1, cBest1) laid the foundational groundwork for establishing the architecture of Best1. Recent progress utilizing single-particle cryogenic electron microscopy has further elucidated the molecular mechanism of gating in cBest1 and, separately, the structure of Best2 from Bos taurus (bovine Best2, bBest2). Meanwhile, whole-cell patch clamp, planar lipid bilayer, and other electrophysiologic analyses using these models, as well as the human Best1 (hBest1), have provided ample evidence describing the functional properties of the bestrophin channels. This review seeks to consolidate these structural and functional results to paint a broad picture of the underlying mechanisms comprising the bestrophin family’s structure-function relationship.

KEYWORDS:

• Bestrophins
• Best1
• Best2
• Bestrophin structure
• Bestrophin function

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

We thank the Unrestricted Grant from Research to Prevent Blindness (RPB) to the Department of Ophthalmology at Columbia University. A.P.O. was supported by NIH (F31EY030763). T.Y. was supported by NIH (R01GM127652 and R24EY028758), Irma T. Hirsch Research Award (CU20-4313) and Schaefer Research Award.