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1.A.33 The Cation Channel-forming Heat Shock Protein-70 (Hsp70) Family

The ubiquitous Hsp70 family includes molecular chaperones that are often found in association with membranes. One member of the Hsp70 family, Hsc70, has been incorporated into artificial lipid bilayers, and it proved to mediate stable transmembrane ion flow. Cation-selective flux occurred in well-defined, multilevel, discrete events suggesting the formation of a multi-conductance ion channel. Channel activity was ATP-dependent and ADP inhibitable (Arispe and DeMaio, 2000). Phloretin, a flavonoid, enhances the pore-forming activity of the chaperone on artificial membranes and increased the efficacy of HSP70 penetration in B16 mouse melanoma cells (Abkin et al. 2016). Cell surface localized Hsp70 binds a 32 kDa serine protease called granzyme B and takes up the protein. Uptake results in the initiation of apoptosis selectively in tumor cells presenting Hsp70 on their surfaces. The same Hsp70 may form cation-specific channels. Hsp70 also promotes cell lysis (Gross et al., 2003).

Eukaryotic members of the Hsp70 family include four well-characterized members: Hsp70, Hsc70, BIP and Mtp70. In all of these proteins, the N-terminal 44 kDa domain hydrolyzes ATP; the central 18 kDa domain interacts with target proteins (the peptide binding domain), and the C-terminal 10 kDa domain functions to allow association with co-chaperone proteins. Binding of ATP and co-chaperone influences peptide recognition while ATP hydrolysis increases the affinity for substrate peptides. Hsp70 and Hsc70 are cystolic, BIP is in the ER matrix, and Mtp70 is in the mitochondrial matrix. All of these proteins function in transmembrane polypeptide translocation. Whether channel formation is physiologically important in cells has not been determined. The MTJ-1 protein plays a role in cell surface translocation of GRP78 which appears to be a receptor for alpha 2-macroglobulin-dependent signaling (Misra et al. 2005).

The outer membranes of Mycobacteria form a thick permeability barrier and provide resistance to many antibiotics. Only few mycolate outer membrane (MOM) proteins have been identified.  One identified MOMP, MMAR_0617 of Mycobacterium marinum ((B2HP37; TC# ), was purified and shown to form a large oligomeric complex with a clear single-channel conductance of 0.8 ± 0.1 ns upon reconstitution into artificial planar lipid bilayers. It has a long C-terminal threonine-rich domain with extensive modifications. It is distantly related to Hsp70 (van der Woude et al. 2013). 

Except for the Mycobacterial MOMP MMAR_0617 protein, there is no evidence that bacterial chaparone proteins of this family form pores.  These chaparone proteins are homologous to proteins involved in capsular polysaccharide export (TC# 9.A.41) and cell shape-determining complexes (TC# 9.B.157).

The transport reaction catalyzed by Hsc70 and MMAR_0617 is:

ions (in) ions (out)

References associated with 1.A.33 family:

Abkin, S.V., O.S. Ostroumova, E.Y. Komarova, D.A. Meshalkina, M.A. Shevtsov, B.A. Margulis, and I.V. Guzhova. (2016). Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma. Cancer Immunol Immunother 65: 83-92. 26646850
Arispe, N. and A. DeMaio. (2000). ATP and ADP modulate a cation channel formed by Hsc70 in acidic phospholipid membranes. J. Biol. Chem. 275: 30839-30843. 10899168
Evensen, N.A., C. Kuscu, H.L. Nguyen, K. Zarrabi, A. Dufour, P. Kadam, Y.J. Hu, A. Pulkoski-Gross, W.F. Bahou, S. Zucker, and J. Cao. (2013). Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst 105: 1402-1416. 23990668
Gross, C., W. Koelch, A. DeMaio, N. Arispe, and G. Multhoff. (2003). Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J. Biol. Chem. 278: 41173-41181. 12874291
Hughes, S.J., T. Antoshchenko, Y. Chen, H. Lu, J.C. Pizarro, and H.W. Park. (2016). Probing the ATP Site of GRP78 with Nucleotide Triphosphate Analogs. PLoS One 11: e0154862. 27144892
Misra, U.K., M. Gonzalez-Gronow, G. Gawdi, and S.V. Pizzo. (2005). The role of MTJ-1 in cell surface translocation of GRP78, a receptor for alpha 2-macroglobulin-dependent signaling. J Immunol 174: 2092-2097. 15699139
Spaan, C.N., R.J. de Boer, W.L. Smit, J.H. van der Meer, M. van Roest, J.L. Vermeulen, P.J. Koelink, M.A. Becker, S. Go, J. Silva, W.J. Faller, G.R. van den Brink, V. Muncan, and J. Heijmans. (2023). Grp78 is required for intestinal Kras-dependent glycolysis proliferation and adenomagenesis. Life Sci Alliance 6:. 37643866
Steel, G.J., D.M. Fullerton, J.R. Tyson, and C.J. Stirling. (2004). Coordinated activation of Hsp70 chaperones. Science 303: 98-101. 14704430
Sukhoplyasova, M., A.M. Keith, E.M. Perrault, H.E. Vorndran, A.S. Jordahl, M.E. Yates, A. Pastor, Z. Li, M.L. Freaney, R.A. Deshpande, D.B. Adams, C.J. Guerriero, S. Shi, T.R. Kleyman, O.B. Kashlan, J.L. Brodsky, and T.M. Buck. (2023). Lhs1 dependent ERAD is determined by transmembrane domain context. Biochem. J. 480: 1459-1473. 37702403
van der Woude, A.D., K.R. Mahendran, R. Ummels, S.R. Piersma, T.V. Pham, C.R. Jiménez, K. de Punder, N.N. van der Wel, M. Winterhalter, J. Luirink, W. Bitter, and E.N. Houben. (2013). Differential detergent extraction of mycobacterium marinum cell envelope proteins identifies an extensively modified threonine-rich outer membrane protein with channel activity. J. Bacteriol. 195: 2050-2059. 23457249