HSP90AA1

Description

The HSP90AA1 (heat shock protein 90 alpha family class A member 1) is a protein-coding gene located on chromosome 14.

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene. The gene, HSP90AA1, encodes the human stress-inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expressed paralog Hsp90B which shares over 85% amino acid sequence identity, Hsp90A expression is initiated when a cell experiences proteotoxic stress. Once expressed Hsp90A dimers operate as molecular chaperones that bind and fold other proteins into their functional 3-dimensional structures. This molecular chaperoning ability of Hsp90A is driven by a cycle of structural rearrangements fueled by ATP hydrolysis. Current research on Hsp90A focuses in its role as a drug target due to its interaction with a large number of tumor promoting proteins and its role in cellular stress adaptation. Human HSP90AA1 is encoded on the complement strand of Chromosome 14q32.33 and spans over 59 kbp. Several pseudogenes of HSP90AA1 exist throughout the human genome located on Chromosomes 3, 4, 11 and 14. The HSP90AA1 gene encodes for two distinct mRNA transcripts initiated from separate transcription start sites (TSS). No mRNA splice variants of HSP90AA1 have presently been verified.

HSP90AA1 is a molecular chaperone that promotes the proper folding, stability, and regulation of specific target proteins involved in essential cellular processes like cell cycle control and signal transduction. It undergoes a functional cycle fueled by its ATPase activity, which is crucial for its chaperone function. This cycle likely induces conformational changes in client proteins, leading to their activation. HSP90AA1 dynamically interacts with various co-chaperones that fine-tune its substrate recognition, ATPase cycle, and chaperone activity. It engages with diverse client protein classes through interactions with co-chaperone proteins or complexes that act as adapters, bridging the gap between the specific client and the central chaperone. The recruitment of ATP and a co-chaperone, followed by the client protein, forms a functional chaperone complex. After successful chaperoning, the properly folded client protein and co-chaperone detach from HSP90 in an ADP-bound, partially open conformation. Finally, ADP is released from HSP90, allowing it to adopt an open conformation for the next chaperone cycle. HSP90AA1 plays a vital role in mitochondrial import, delivering preproteins to the mitochondrial import receptor TOMM70. Beyond its chaperone activity, HSP90AA1 participates in regulating the transcription machinery. HSP90AA1 and its co-chaperones modulate transcription at multiple levels: by altering the steady-state levels of certain transcription factors in response to physiological cues, by modulating the activity of epigenetic modifiers like histone deacetylases or DNA methyl transferases, and by participating in histone eviction from promoter regions, thus turning on gene expression. HSP90AA1 binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory responses, including TNF secretion by monocytes. It antagonizes the inhibition of TGF-beta signaling by STUB1 by inhibiting the STUB1-mediated ubiquitination and degradation of SMAD3. HSP90AA1 mediates the association of TOMM70 with IRF3 or TBK1 in the mitochondrial outer membrane, promoting the host's antiviral response.

HSP90AA1 is also known as EL52, HEL-S-65p, HSP86, HSP89A, HSP90A, HSP90N, HSPC1, HSPCA, HSPCAL1, HSPCAL4, HSPN, Hsp103, Hsp89, Hsp90, LAP-2, LAP2.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing