NDLI: Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Su, Ya Blake-Palmer, Katherine G. Sorrell, Sara Javid, Babak Bowers, Katherine Zhou, Aiwu Chang, Simon H. Qamar, Seema Karet, Fiona E.
Description	Country affiliation: United kingdom Author Affiliation: Su Y ( Department of Medical Genetics, Cambridge University, Cambridge Institute for Medical Research, Addenbrooke's Hospital Box 139, Cambridge, CB2 0XY, UK.)
Abstract	The vacuolar-type ATPase (H+ATPase) is a ubiquitously expressed multisubunit pump whose regulation is poorly understood. Its membrane-integral a-subunit is involved in proton translocation and in humans has four forms, a1-a4. This study investigated two naturally occurring point mutations in a4's COOH terminus that cause recessive distal renal tubular acidosis (dRTA), R807Q and G820R. Both lie within a domain that binds the glycolytic enzyme phosphofructokinase-1 (PFK-1). We recreated these disease mutations in yeast to investigate effects on protein expression, H+ATPase assembly, targeting and activity, and performed in vitro PFK-1 binding and activity studies of mammalian proteins. Mammalian studies revealed complete loss of binding between the COOH terminus of a4 containing the G-to-R mutant and PFK-1, without affecting PFK-1's catalytic activity. In yeast expression studies, protein levels, H+ATPase assembly, and targeting of this mutant were all preserved. However, severe (78%) loss of proton transport but less decrease in ATPase activity (36%) were observed in mutant vacuoles, suggesting a requirement for the a-subunit/PFK-1 binding to couple these two functions. This role for PFK in H+ATPase function was supported by similar functional losses and uncoupling ratio between the two proton pump domains observed in vacuoles from a PFK-null strain, which was also unable to grow at alkaline pH. In contrast, the R-to-Q mutation dramatically reduced a-subunit production, abolishing H+ATPase function completely. Thus in the context of dRTA, stability and function of the metabolon composed of H+ATPase and glycolytic components can be compromised by either loss of required PFK-1 binding (G820R) or loss of pump protein (R807Q).
File Format	HTM / HTML
ISSN	1931857X
e-ISSN	15221466
DOI	10.1152/ajprenal.90258.2008
Journal	AJP: Renal Physiology
Issue Number	4
Volume Number	295
Language	English
Publisher	American Physiological Society
Publisher Date	2008-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Surface Plasmon Resonance Amino Acid Sequence Protein Subunits Research Support, Non-u.s. Gov't Saccharomyces Cerevisiae Proteins Molecular Sequence Data Discipline Nephrology Metabolism Mutagenesis, Site-directed Physiopathology Saccharomyces Cerevisiae Discipline Physiology Phosphofructokinase-1 Acidosis, Renal Tubular Proton-translocating Atpases Glycolysis Genetics Physiology Circular Dichroism Vacuolar Proton-translocating Atpases
Content Type	Text
Resource Type	Article
Subject	Physiology Urology

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Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1

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