The role of Aha1 in cancer and neurodegeneration

Abstract

The 90 kDa Heat shock protein (Hsp90) is a family of ubiquitously expressed molecular chaperones responsible for the stabilization and maturation of >400 client proteins. Hsp90 exhibits dramatic conformational changes to accomplish this, which are regulated by partner proteins termed co-chaperones. One of these co-chaperones is called the activator or Hsp90 ATPase activity homolog 1 (Aha1) and is the most potent accelerator of Hsp90 ATPase activity. In conditions where Aha1 levels are dysregulated including cystic fibrosis, cancer and neurodegeneration, Hsp90 mediated client maturation is disrupted. Accumulating evidence has demonstrated that many disease states exhibit large hetero-protein complexes with Hsp90 as the center. Many of these include Aha1, where increased Aha1 levels drive disease states forward. One strategy to block these effects is to design small molecule disruptors of the Hsp90/Aha1 complex. Studies have demonstrated that current Hsp90/Aha1 small molecule disruptors are effective in both models for cancer and neurodegeration.

Keywords: Aha1; Hsp90; cancer; protein–protein interaction; small molecule; tauopathy.

Figure 1

(A) The structure of Hsc82, the S. cerevisiae Hsp90 homolog in cyan and Aha1 in magenta are shown above with the Hsp90 NTD, MD and CTD labeled are shown for one protomer PDB 6XLF. (B) The MD of Hsp90 (cyan) with Aha1 (magenta) are shown with the Hsp90 catalytic loop (yellow), residues 370–390. (C) The unidirectional model of the Hsp90 chaperone cycle is depicted where co-chaperones like Aha1 drive the cycle, ATP hydrolysis and client maturation forward.

Figure 2

Recent Hsp90 chaperone model depicting four states in a population model, Hsp90 open, short lived Hsp90 open, short lived Hsp90 closed and Hsp90 closed. The initial three states are in “delicate balance,” where introducing ATP, Sba1 and Aha1 significantly increased ATP hydrolysis that is tied to client maturation. The final state includes all five components and is removed from the cycle in “steady state.”

Figure 3

The recruitment and displacement of various co-chaperones that move the Hsp90 cycle forward depends upon post-translational modifications that enhance or hinder these interactions as shown in the figure above.

Figure 4

Cartoon depicting the mechanisms by which Aha1 overexpression mediates increased proliferation, invasion, EMT progression and subsequent metastasis in osteosarcoma.

Figure 5

Cartoon schematic of mechanisms by which Aha1 induces proliferation and invasion in HCC is shown above.

Figure 6

Comparison between the effects of Aha1 overexpression in neurodegenerative diseases and cancer.

Figure 7

The Hsp90/Aha1 accelerate the aggregation of tau oligomers and neurofibrillary tangles. Hsp90/Aha1 is hypothesized to accelerate α-Synuclein aggregation.