Molecular mechanisms of cutis laxa– and distal renal tubular acidosis–causing mutations in V-ATPase a subunits, ATP6V0A2 and ATP6V0A4

Abstract

The a subunit is the largest of 15 different subunits that make up the vacuolar H + -ATPase (V-ATPase) complex, where it functions in proton translocation. In mammals, this subunit has four paralogous isoforms, a1-a4, which may encode signals for targeting assembled VATPases to specific intracellular locations. Despite the functional importance of the a subunit, its structure remains controversial. By studying molecular mechanisms of human disease-causing missense mutations within a subunit isoforms, we may identify domains critical for V-ATPase targeting, activity and/or regulation.cDNA . Coimmunoprecipitation studies revealed an increase in association of a4 R449H with the V0 assembly factor VMA21, and a reduced association with the V1 sector subunit, ATP6V1B1 (B1). For a4 G820R , where stability, degradation and trafficking were relatively unaffected, 3D molecular modeling suggested that the mutation causes dRTA by blocking the proton pathway. This study provides critical information that may assist rational drug design to manage dRTA and cutis laxa. Vacuolar H+ -ATPases (V-ATPases) are conserved, multisubunit rotary proton pumps that play crucial roles in regulating the pH of cells and their intracellular compartments (1-5). They can be categorized as endomembrane or plasma membrane V-ATPases, based on their subcellular localization (6,7). Endomembrane V-ATPases are expressed in all eukaryotic cells in the membranes of acidic organelles like lysosomes, endosomes and the Golgi apparatus, where they translocate protons to acidify the luminal compartments of the organelles (8). Plasma membrane V-ATPases traffic to the surfaces of some specialized cells, such as osteoclasts, kidney intercalated cells and metastatic cancer cells, where they secrete protons into the extracellular fluid (6,9-11).The V-ATPase complex consists of 15 different subunits arranged into two major sectors, the http://www.jbc.org/cgi

Vacuolar-type ATPase: A proton pump to lysosomal trafficking

“…Mutation of a 4 causes distal tubular acidosis accompanied by hearing loss and enlarged morphology of the inner ear. 46,47) In addition to subunit a , the V O subunit d has d 1 and d 2 isoforms; 48,49) d 1 is ubiquitous, whereas d 2 is specific for osteoclasts. 50) The function of subunits a and d in organelle trafficking is discussed below (sections 3 and 4).…”

“…4,7) B 1 is expressed specifically in the kidney, epididymis, and hair cells of the inner ear, whereas B 2 is expressed ubiquitously. Mutations in the human B 1 gene ( ATP6V1B1 ) or a 4 isoform ( ATP6V0A4 ) cause distal renal tubular acidosis with sensorineural deafness in humans, 47,51) suggesting that V-ATPase with B 1 and a 4 expressed in renal and hair cells is essential for the regulation of acid/base homeostasis and ion transport required for hearing, respectively. 4)…”

Histone deacetylase–mediated regulation of endolysosomal pH

“…osteopetrosis, renal tubular acidosis, cutis laxa), chloride transporters (e.g. Dent's disease), and eNHE (Christianson syndrome, autism, and attention deficit hyperactivity disorder) (3,4,6). Furthermore, defective endolysosomal pH regulation is being increasingly linked to cellular aging, amyloidogenesis, synaptic dysfunction, and neurodegenerative disorders, including Alzheimer's disease (7,8).…”

V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis

“…V-ATPase complex plays a significant role in biological and physiological processes. Mutations in the coding genes and non-coding regions of V-ATPase subunits cause various syndromes 44 , 45 . The subunits of V-ATPase are ubiquitously expressed, and some of them have tissue or cell-specific distributions.…”