ACTIVATOR OF HEAT-SHOCK 90-KD PROTEIN ATPase 1; AHSA1

Alternative titles; symbols

• AHA1

HGNC Approved Gene Symbol: AHSA1

Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:77,457,866-77,469,471 (from NCBI)

▼ Cloning and Expression
The vesicular stomatitis virus glycoprotein (VSVG) is a model transmembrane glycoprotein used to study the exocytotic pathway. Using the protein-sorting motifs in the VSVG tail as bait in a yeast 2-hybrid screen of a HeLa cell cDNA library, followed by EST database analysis, Sevier and Machamer (2001) cloned AHSA1, which they called p38. The deduced 338-amino acid protein has a calculated molecular mass of 38.3 kD. Northern blot analysis detected a 1.5-kb transcript in brain, heart, skeletal muscle, and kidney; lower levels were detected in liver and placenta. Expression was below the level of detection in colon, thymus, spleen, small intestine, lung, and peripheral blood leukocytes. However, the authors identified AHSA1 sequences in colon, thymus, small intestine, lung, and blood EST databases, suggesting that AHSA1 expression is ubiquitous but variable. Western blot analysis detected endogenous AHSA1 at an apparent molecular mass of 40 kD in HeLa cells. AHSA1 was primarily found in the cytosolic fraction of HeLa cell homogenates, with some in the microsomal membrane pellet. Immunofluorescence microscopy revealed strong cytosolic staining. When proteins were crosslinked prior to visualization, AHSA1 staining showed a more reticular pattern, suggesting that the crosslinker may have stabilized an association of AHSA1 with a tethering protein in the endoplasmic reticulum membrane.

By searching databases for sequences similar to an S. cerevisiae Hsp90 (140571) suppressor, Hch1, Lotz et al. (2003) identified AHSA1. The deduced protein contains a putative N-terminal domain that is homologous to Hch1 and a putative C-terminal domain.

▼ Gene Function
Lotz et al. (2003) determined that interaction of HSP90 and AHSA1 required a region of HSP90 that links its N-terminal and middle domains. They found that AHSA1 stimulated the intrinsic ATPase activity of HSP90 5-fold.

Cystic fibrosis (CF; 219700) is an inherited childhood disease primarily triggered by defective folding and export of the CFTR (606421) protein from the endoplasmic reticulum (ER). Using proteomics to assess global CFTR protein interactions, Wang et al. (2006) showed that HSP90 cochaperones modulated HSP90-dependent stability of CFTR protein folding in the ER. Small interfering RNA-mediated partial silencing of the HSP90 cochaperone AHA1 in human embryonic kidney and lung cell lines rescued delivery of the most common disease-causing ER-restricted CFTR delta-F508 variant (602421.0001) to the cell surface. Wang et al. (2006) proposed that failure of CFTR delta-F508 to achieve an energetically favorable fold in response to steady-state dynamics of the chaperone folding environment is responsible for the pathophysiology of CF.

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the AHSA1 gene to chromosome 14 (WI-15374).