Table 2 The HTT-HAP40 complex: unlocking the secrets of a duo.
From: Huntingtin and its allies at the cortico-striatal synapse
Discovery and abundance | |
|---|---|
HAP40 was identified through its ability to co-immunoprecipitate with full-length HTT from rat brain extracts. | [196] |
HAP40 is established as the most abundant HTT interactor in the mouse brain. | |
Structure and evolution | |
Structure of the HTT-HAP40 complex is resolved at high resolution by cryo-EM. | [197] |
Strong co-evolution between HTT and HAP40 supports the functional importance of the HTT-HAP40 complex. | [198] |
HAP40 stabilizes HTT which adopts a compact, globular conformation with three domains: N-terminal HEAT-repeat (N-HEAT), central bridge domain and C-terminal HEAT-repeat (C-HEAT). | |
HAP40 is enclosed between the N- and C-HEAT domains of HTT and binds preferentially to its C-terminal region, with ten evolutionary conserved intermolecular contacts that stabilize the complex. | [200] |
HTT and HAP40 form an obligate heteromeric complex. Loss of HTT causes rapid proteasomal degradation of HAP40, while loss of HAP40 determines reduced HTT stability. | |
Role in Huntington’s disease | |
Structural studies indicate minimal effects of the expanded polyQ tract on HTT–HAP40 architecture and stability. | |
Co-immunoprecipitation studies revealed increased binding of HAP40 to mutant HTT in the brains of HD knock-in mice. | [202] |
HTT-HAP40 complex is implicated in protein degradation via the ubiquitin-proteasome system. | |
HAP40 depletion in HD mice exacerbates mutant HTT aggregation and neuronal loss, whereas HAP40 overexpression reduces aggregation and ameliorates behavioural deficits. | [202] |
