This gene encodes a 70kDa heat shock protein and is located in themajor histocompatibility complex class III region, in a cluster with two closely related genes which also encodeisoforms of the 70kDa heat shock protein.[7] Theamino acid sequence of the encoded protein shares a 90% homology to the isoformsHSPA1A andHSPA1B.[11] As a Hsp70 protein, it has aC-terminal protein substrate-binding domain and anN-terminalATP-binding domain.[12][13][14][15] The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket.[14] The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical forallosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site forco-chaperones.[14][15]
Since acDNA clone of this gene contains a 119 bp-region in the5' UTR, it is likely thatHSPA1L contains one or moreintrons in its own 5' UTR.[11]
In general, HSPA1L is widely distributed across tissues at low abundances, but in particular, it is constitutively and abundantly expressed in thetestis.[15][16]
Along with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in thecytosol and inorganelles.[8][9] In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of freesubstrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[8][9]
In addition to the process of protein folding, transport and degradation, this Hsp70 member can preserve the function of mutant proteins. Nonetheless, effects of these mutations can still manifest when Hsp70 chaperones are overwhelmed during stress conditions.[8] Furthermore, this protein enhancesantigen-specific tumor immunity by facilitating more efficient antigen presentation tocytotoxic T cells.[9] Though it shares close homology to HSPA1A and HSPA1B, it is regulated differently and is not heat-inducible.[11]
The Hsp70 member proteins are important apoptotic constituents. During a normalembryologic processes, or during cell injury (such as ischemia-reperfusion injury duringheart attacks andstrokes) or during developments and processes incancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of theDNA andnucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed byphagocytes, thereby preventing aninflammatory response.[17] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role oppositemitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance ofnecrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in manyphysiological andpathological processes. It plays an important role duringembryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on thecaspase-dependent pathway and against apoptosis-inducing agents such astumor necrosis factor-α (TNFα),staurosporine, anddoxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such ashepatocellular carcinoma,gastric cancers,colon cancers,breast cancers, andlung cancers, which led to its use as aprognosticmarker for these cancers.[9] Elevated Hsp70 levels in tumor cells may increasemalignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[8][9] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[9] Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such asAlzheimer's disease,Parkinson's disease (PD),Huntington's disease, andspinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[8] HSPA1L may fight against PD by co-regulating thetranslocation ofparkin to damagedmitochondria, thus facilitating their removal.[16]
HSPA1L is also involved in Graft-versus-host disease (GVHD) and has potential to serve as a diagnostic/prognostic biomarker.[10]Polymorphisms in theHSPA1L gene, especially those in the substrate binding domain, have been associated with disease.[15]
^abcdefghWang X, Wang Q, Lin H, Li S, Sun L, Yang Y (Feb 2013). "HSP72 and gp96 in gastroenterological cancers".Clinica Chimica Acta; International Journal of Clinical Chemistry.417:73–9.doi:10.1016/j.cca.2012.12.017.PMID23266770.
^abAtarod S, Turner B, Pearce KF, Ahmed SS, Norden J, Bogunia-Kubik K, Wang XN, Collin M, Dickinson AM (Feb 2015). "Elevated level of HSPA1L mRNA correlates with graft-versus-host disease".Transplant Immunology.32 (3):188–94.doi:10.1016/j.trim.2015.02.002.PMID25680846.
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Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200 (1–2):149–56.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
Schröder O, Schulte KM, Ostermann P, Röher HD, Ekkernkamp A, Laun RA (Jan 2003). "Heat shock protein 70 genotypes HSPA1B and HSPA1L influence cytokine concentrations and interfere with outcome after major injury".Critical Care Medicine.31 (1):73–9.doi:10.1097/00003246-200301000-00011.PMID12544996.S2CID30753801.
