Intracellular proteins are targeted for proteolytic degradation in the lysosome with the aid of chaperones. Heat shock cognate 71 kDa protein (HSPA8) acts as the constitutive chaperone that binds KFERQ-domain containing substrates in the cytosol. Consequently, the HSPA8:Substrate complex translocates from cytosol to lysosomal membrane where it binds to Lysosome-associated membrane glycoprotein 2 (LAMP2a). Subsequently, HSPA8 is released and Heat shock protein HSP 90 binds to the lysosomal luminal end of LAMP2a. This LAMP2a complex then multimerizes into a 700 kDa entity and is stabilized by the binding of Glial fibrillary acidic protein (GFAP) (Bandyopadhyay U et al. 2010). Subsequently, the substrate is unfolded and internalized into the lumen. Experiments confirming this binding were performed on rat models.
Cuervo, AM, Kiffin, R, Sridhar, S, Kaushik, S, Bandyopadhyay, U
Cuervo, AM, Kiffin, R, Kon, M, Sridhar, S, Bandyopadhyay, U, Kaushik, S, Wong, E, Orenstein, SJ, Martinez-Vicente, M
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