Human HSPA4 (also known as 70kDa heat shock protein 4, APG-2, HS24/P52, hsp70 RY, and HSPH2) responds to acidic pH stress, is involved in the radioadaptive response, is required for normal spermatogenesis and is overexpressed in hepatocellular carcinoma [, , ]. It participates in a pathway along with NBS1 (Nijmegen breakage syndrome 1, also known as p85 or nibrin), heat shock transcription factor 4b (HDF4b), and HSPA14 (belonging to a different HSP70 subfamily) that induces tumor migration, invasion, and transformation []. HSPA4 expression in sperm was increased in men with oligozoospermia, especially in those with varicocele []. HSPA4 belongs to the 105/110kDa heat shock protein (HSP105/110) subfamily of the HSP70-like family []. HSP105/110s are believed to function generally as co-chaperones of HSP70 chaperones, acting as nucleotide exchange factors (NEFs), to remove ADP from their HSP70 chaperone partners during the ATP hydrolysis cycle. HSP70 chaperones assist in protein folding and assembly, and can direct incompetent 'client' proteins towards degradation. Like HSP70 chaperones, HSP105/110s have an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD) [].This entry represents the N-terminal nucleotide-binding domain of HSPA4.
Human HSPA14 (also known as 70kDa heat shock protein 14 or HSP70L1), is ribosome-associated and belongs to the heat shock protein 70 (HSP70) family of chaperones that assist in protein folding and assembly, and can direct incompetent 'client' proteins towards degradation. Typically, HSP70s have a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. The two subdomains of each lobe change conformation between ATP-bound, ADP-bound, and nucleotide-free states. ATP binding opens up the substrate-binding site; substrate-binding increases the rate of ATP hydrolysis. HSP70 chaperone activity is regulated by various co-chaperones: J-domain proteins and nucleotide exchange factors (NEFs). HSPA14 interacts with the J-protein MPP11 to form the mammalian ribosome-associated complex (mRAC) []. HSPA14 participates in a pathway along with Nijmegen breakage syndrome 1 (NBS1, also known as p85 or nibrin), heat shock transcription factor 4b (HSF4b), and HSPA4 (belonging to a different subfamily), that induces tumor migration, invasion, and transformation []. HSPA14 is a potent T helper cell (Th1) polarizing adjuvant that contributes to antitumor immune responses [, ].
