HSPA1L

Last updated
HSPA1L
Protein HSPA1L PDB 1hjo.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HSPA1L , HSP70-1L, HSP70-HOM, HSP70T, hum70t, heat shock protein family A (Hsp70) member 1 like
External IDs OMIM: 140559 MGI: 96231 HomoloGene: 135835 GeneCards: HSPA1L
Orthologs
SpeciesHumanMouse
Entrez

3305

15482

Ensembl

ENSMUSG00000007033

UniProt

P34931

P16627

RefSeq (mRNA)

NM_005527

NM_013558

RefSeq (protein)

NP_005518

NP_038586

Location (UCSC) Chr 6: 31.81 – 31.82 Mb Chr 17: 35.19 – 35.2 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene on chromosome 6. [5] [6] [7] As a member of the heat shock protein 70 (Hsp70) family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. [7] [8] Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. [8] [9] It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and Graft-versus-host disease. [8] [9] [10]

Contents

Structure

This gene encodes a 70kDa heat shock protein and is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein. [7] The amino acid sequence of the encoded protein shares a 90% homology to the isoforms HSPA1A and HSPA1B. [11] As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-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 for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones. [14] [15]

Since a cDNA clone of this gene contains a 119 bp-region in the 5' UTR, it is likely that HSPA1L contains one or more introns in its own 5' UTR. [11]

Function

In general, HSPA1L is widely distributed across tissues at low abundances, but in particular, it is constitutively and abundantly expressed in the testis. [15] [16]

Along with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. [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 free substrate. 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 enhances antigen-specific tumor immunity by facilitating more efficient antigen presentation to cytotoxic T cells. [9] Though it shares close homology to HSPA1A and HSPA1B, it is regulated differently and is not heat-inducible. [11]

Clinical significance

The Hsp70 member proteins are important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory 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 opposite mitosis 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 of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal 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 the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. 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 as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers. [9] Elevated Hsp70 levels in tumor cells may increase malignancy 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 as Alzheimer's disease, Parkinson's disease (PD), Huntington's disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge. [8] HSPA1L may fight against PD by co-regulating the translocation of parkin to damaged mitochondria, 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 the HSPA1L gene, especially those in the substrate binding domain, have been associated with disease. [15]

Interactions

HSPA1L has been shown to interact with PARK2. [16]

Related Research Articles

<span class="mw-page-title-main">Chaperone (protein)</span> Proteins assisting in protein folding

In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.

<span class="mw-page-title-main">Hsp70</span> Family of heat shock proteins

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

<span class="mw-page-title-main">Hsp90</span> Heat shock proteins with a molecular mass around 90kDa

Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.

<span class="mw-page-title-main">GroEL</span> Protein-coding gene in the species Homo sapiens

GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the organellar proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively, due to their endosymbiotic origin.

<span class="mw-page-title-main">HSPA8</span> Protein-coding gene in the species Homo sapiens

Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.

<span class="mw-page-title-main">Hsp27</span> Protein-coding gene in the species Homo sapiens

Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the HSPB1 gene.

<span class="mw-page-title-main">HSPA1A</span> Protein-coding gene in the species Homo sapiens

Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.

<span class="mw-page-title-main">Heat shock protein 90kDa alpha (cytosolic), member A1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.

<span class="mw-page-title-main">HSPA1B</span> Human gene

Human gene HSPA1B is an intron-less gene which encodes for the heat shock protein HSP70-2, a member of the Hsp70 family of proteins. The gene is located in the major histocompatibility complex, on the short arm of chromosome 6, in a cluster with two paralogous genes, HSPA1A and HSPA1L. HSPA1A and HSPA1B produce nearly identical proteins because the few differences in their DNA sequences are almost exclusively synonymous substitutions or in the three prime untranslated region, heat shock 70kDa protein 1A, from HSPA1A, and heat shock 70kDa protein 1B, from HSPA1B. A third, more modified paralog to these genes exists in the same region, HSPA1L, which shares a 90% homology with the other two.

<span class="mw-page-title-main">HSF1</span> Protein-coding gene in the species Homo sapiens

Heat shock factor 1 is a protein that in humans is encoded by the HSF1 gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.

<span class="mw-page-title-main">BAG1</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.

<span class="mw-page-title-main">HSP90AB1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.

<span class="mw-page-title-main">DNAJA3</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.

<span class="mw-page-title-main">Binding immunoglobulin protein</span> Protein-coding gene in the species Homo sapiens

Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.

<span class="mw-page-title-main">Peptidylprolyl isomerase D</span> Protein-coding gene in the species Homo sapiens

Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an enzyme which in humans is encoded by the PPID gene on chromosome 4. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPID participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.

<span class="mw-page-title-main">BAG4</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 4 is a protein that in humans is encoded by the BAG4 gene.

<span class="mw-page-title-main">BAG5</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 5 is a protein that in humans is encoded by the BAG5 gene.

<span class="mw-page-title-main">Chaperone DnaJ</span> Molecular chaperone protein

In molecular biology, chaperone DnaJ, also known as Hsp40, is a molecular chaperone protein. It is expressed in a wide variety of organisms from bacteria to humans.

<span class="mw-page-title-main">GrpE</span> InterPro Family

GrpE is a bacterial nucleotide exchange factor that is important for regulation of protein folding machinery, as well as the heat shock response. It is a heat-inducible protein and during stress it prevents unfolded proteins from accumulating in the cytoplasm. Accumulation of unfolded proteins in the cytoplasm can lead to cell death.

References

  1. 1 2 3 ENSG00000226704, ENSG00000236251, ENSG00000204390, ENSG00000206383 GRCh38: Ensembl release 89: ENSG00000234258, ENSG00000226704, ENSG00000236251, ENSG00000204390, ENSG00000206383 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000007033 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Ito Y, Ando A, Ando H, Ando J, Saijoh Y, Inoko H, Fujimoto H (Aug 1998). "Genomic structure of the spermatid-specific hsp70 homolog gene located in the class III region of the major histocompatibility complex of mouse and man". Journal of Biochemistry. 124 (2): 347–53. doi:10.1093/oxfordjournals.jbchem.a022118. PMID   9685725.
  6. ↑ Ishihara M, Ohno S (Nov 1997). "Genetic influences on sarcoidosis". Eye. 11. 11 (2): 155–61. doi: 10.1038/eye.1997.44 . PMID   9349405.
  7. 1 2 3 "Entrez Gene: HSPA1L heat shock 70kDa protein 1-like".
  8. 1 2 3 4 5 6 7 8 Mayer MP, Bukau B (Mar 2005). "Hsp70 chaperones: cellular functions and molecular mechanism". Cellular and Molecular Life Sciences. 62 (6): 670–684. doi:10.1007/s00018-004-4464-6. PMC   2773841 . PMID   15770419.
  9. 1 2 3 4 5 6 7 8 Wang 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. PMID   23266770.
  10. 1 2 Atarod 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. PMID   25680846.
  11. 1 2 3 Ito Y, Ando A, Ando H, Ando J, Saijoh Y, Inoko H, Fujimoto H (Aug 1998). "Genomic structure of the spermatid-specific hsp70 homolog gene located in the class III region of the major histocompatibility complex of mouse and man". Journal of Biochemistry. 124 (2): 347–53. doi:10.1093/oxfordjournals.jbchem.a022118. PMID   9685725.
  12. ↑ Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G (September 2001). "Heat-shock protein 70 antagonizes apoptosis-inducing factor". Nat. Cell Biol. 3 (9): 839–43. doi:10.1038/ncb0901-839. PMID   11533664. S2CID   21164493.
  13. ↑ Zhang B, Rong R, Li H, Peng X, Xiong L, Wang Y, Yu X, Mao H (2015). "Heat shock protein 72 suppresses apoptosis by increasing the stability of X-linked inhibitor of apoptosis protein in renal ischemia/reperfusion injury". Mol Med Rep. 11 (3): 1793–9. doi:10.3892/mmr.2014.2939. PMC   4270332 . PMID   25394481.
  14. 1 2 3 Zhang P, Leu JI, Murphy ME, George DL, Marmorstein R (2014). "Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate". PLOS ONE. 9 (7): e103518. Bibcode:2014PLoSO...9j3518Z. doi: 10.1371/journal.pone.0103518 . PMC   4110032 . PMID   25058147.
  15. 1 2 3 4 Wisniewska M, Karlberg T, Lehtiö L, Johansson I, Kotenyova T, Moche M, Schüler H (11 January 2010). "Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78". PLOS ONE. 5 (1): e8625. Bibcode:2010PLoSO...5.8625W. doi: 10.1371/journal.pone.0008625 . PMC   2803158 . PMID   20072699.
  16. 1 2 3 Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, Wang C, Heman-Ackah SM, Hessa T, Guha R, Martin SE, Youle RJ (Dec 2013). "High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy". Nature. 504 (7479): 291–5. Bibcode:2013Natur.504..291H. doi:10.1038/nature12748. PMC   5841086 . PMID   24270810.
  17. ↑ Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC   2008650 . PMID   4561027.

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