Bestrophin 1

743924115ENSG00000167995ENSMUSG00000037418O76090O88870NM_001363592NM_001363593NM_011913NP_001350521NP_001350522NP_036043Bestrophin-1 (Best1) is a protein that, in humans, is encoded by the BEST1 gene (RPD ID - 5T5N/4RDQ). Bestrophin-1 (Best1) is a protein that, in humans, is encoded by the BEST1 gene (RPD ID - 5T5N/4RDQ). The bestrophin family of proteins comprises four evolutionary related genes (BEST1, BEST2, BEST3, and BEST4) that code for integral membrane proteins. This family was first identified in humans by linking a BEST1 mutation with Best vitelliform macular dystrophy (BVMD). Mutations in the BEST1 gene have been identified as the primary cause for at least five different degenerative retinal diseases. The bestrophins are an ancient family of structurally conserved proteins that have been identified in nearly every organism studied from bacteria to humans. In humans, they function as calcium-activated anion channels, each of which has a unique tissue distribution throughout the body. Specifically, the BEST1 gene on chromosome 11q13 encodes the Bestrophin-1 protein in humans whose expression is highest in the retina. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the four bestrophin genes has a unique 3-prime end of variable length. BEST1 has been shown by two independent studies to be regulated by Microphthalmia-associated transcription factor. Bestrophin-1 is an integral membrane protein found primarily in the retinal pigment epithelium (RPE) of the eye. Within the RPE layer, it is mainly located on the basolateral plasma membrane. Protein crystallization structures indicate this protein's primary ion channel function as well as its calcium regulatory capabilities. Bestrophin-1 consists of 585 amino acids and both N- and the C-termini are located within the cell. The structure of Best1 consists of five identical subunits that each span the membrane four times and form a continuous, funnel-shaped pore via the second transmembrane domain containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The pore is lined with various nonpolar, hydrophobic amino acids. Both the structure and the composition of the pore help to ensure that only small anions are able to move completely through the channel. The channel acts as two funnels working together in tandem. It begins with a semi-selective, narrow entryway for anions, and then opens to a larger, positively charged area which then leads to a narrower pathway that further limits the size of anions passing through the pore. A calcium clasp acts as a belting mechanism around the larger, middle section of the channel. Calcium ions control the opening and closing of the channel due to conformational changes caused by calcium binding at the C-terminus directly following the last transmembrane domain. The location of expression of the BEST1 gene is essential for protein functioning and mislocalization is often connected to a variety of retinal degenerative diseases. The BEST1 gene expresses the Best1 protein primarily in the cytosol of the retinal pigment epithelium. The protein is typically contained in vesicles near the cellular membrane. There is also research to support that the Best1 protein is localized and produced in the endoplasmic reticulum (intracellular organelle involved in protein and lipid synthesis). Best1 is typically expressed with other proteins also synthesized in the endoplasmic reticulum, such as calreticulin, calnexin and Stim-1. Calcium ion involvement in the countertransport of chloride ions also supports the idea that Best1 is involved in forming calcium stores within the cell. Best1 primarily functions as an intracellular calcium-activated chloride channel on the cellular membrane that is not voltage-dependent. More recently Best1 has been shown to act as a volume-regulating anion channel.