The ATPase Domain of hsp70 Possesses a Unique Binding Specificity for 3′-Sulfogalactolipids

The region(s) of hsp70 critical for sulfogalactolipid (SGL) recognition has been defined through deletion analysis and site-directed mutagenesis. Truncated polymerase chain reaction products of hsp70 generated N-terminal fragments of 43, 35, 29, and 22 kDa. The C terminus substrate-binding domain (28 kDa) was also expressed. The N-terminal ATPase domain (rP43) shared the binding specificity of hsp70, because only sulfogalactosyl ceramide and sulfogalactosyl glycerolipid were recognized by both TLC overlay and RELISA. The C-terminal domain showed no binding. SGL binding of rP29 and rP22 was severely reduced. The loss of SGL binding for rP35 by RELISA but not TLC overlay was considered as a function of receptor presentation. The truncation of rP43 to rP35 demonstrates that residues 318–387 (the base of the ATP binding cleft) are critical for high affinity SGL binding. Mutagenesis showed that Arg342 and Phe198 are crucial for this process. SGL binding, mediated by these conserved residues within the ATPase domain of hsp70, implies that this binding specificity is evolutionarily conserved. The region(s) of hsp70 critical for sulfogalactolipid (SGL) recognition has been defined through deletion analysis and site-directed mutagenesis. Truncated polymerase chain reaction products of hsp70 generated N-terminal fragments of 43, 35, 29, and 22 kDa. The C terminus substrate-binding domain (28 kDa) was also expressed. The N-terminal ATPase domain (rP43) shared the binding specificity of hsp70, because only sulfogalactosyl ceramide and sulfogalactosyl glycerolipid were recognized by both TLC overlay and RELISA. The C-terminal domain showed no binding. SGL binding of rP29 and rP22 was severely reduced. The loss of SGL binding for rP35 by RELISA but not TLC overlay was considered as a function of receptor presentation. The truncation of rP43 to rP35 demonstrates that residues 318–387 (the base of the ATP binding cleft) are critical for high affinity SGL binding. Mutagenesis showed that Arg342 and Phe198 are crucial for this process. SGL binding, mediated by these conserved residues within the ATPase domain of hsp70, implies that this binding specificity is evolutionarily conserved. 3′-sulfogalactosyl ceramide sulfogalactolipid 3′-sulfogalactosylglycerolipid 2-(N-morpholino)ethanesulfonic acid Tris-buffered saline polyisobutylmethacrylate galactosylceramide monosialylgangliotetraosyl ceramide gangliotriaosyl ceramide globotetraosyl ceramide globopentaosyl ceramide (Forrsman antigen) receptor enzyme-linked immunosorbent assay Heat shock proteins of the 70-kDa family (hsp70) have traditionally been described as intracellular chaperones that facilitate protein folding (1Beckmann R.P. Mizzen L.E. Welch W.J. Science. 1990; 248: 850-854Crossref PubMed Scopus (1039) Google Scholar), degradation (2Chiang H.L. Terlecky S.R. Plant C.P. Dice J.F. Science. 1989; 246: 382-385Crossref PubMed Scopus (690) Google Scholar), translocation across membranes (3Chirico W.J. Waters M.G. Blobel G. Nature. 1988; 332: 805-810Crossref PubMed Scopus (829) Google Scholar), and disassembly of protein oligomers (4DeLuca-Flaherty F.C. McKay D.B. Parham P. Hill B.L. Cell. 1990; 62: 875-887Abstract Full Text PDF PubMed Scopus (132) Google Scholar). These functions are driven by ATPase activity contained within the N-terminal domain of all hsp70 family members (5Bukau B. Horwich A.L. Cell. 1998; 92: 351-366Abstract Full Text Full Text PDF PubMed Scopus (2397) Google Scholar). Hsp70s have also been described on the surface of bacteria (6Raulston J.E. Davis C.H. Schmiel D.H. Morgan M.W. Wyrick P.B. J. Biol. Chem. 1993; 268: 23139-23147Abstract Full Text PDF PubMed Google Scholar, 7Bukau B. Reilly P. McCarty J. Walker G.C. J. Gen. Microbiol. 1993; 139: 95-99Crossref PubMed Scopus (38) Google Scholar, 8Scorpio A. Johnson P. Laquerre A. Nelson D. J. Bacteriol. 1994; 176: 6449-6456Crossref PubMed Google Scholar, 9Macellaro A. Tujulin E. Hjalmarsson K. Norlander L. Infect. Immun. 1998; 66: 5882-5888Crossref PubMed Google Scholar), male germ cells (10Miller D. Brough S. Al-Harbi O. Hum. Reprod. 1992; 7: 637-645Crossref PubMed Scopus (68) Google Scholar), and carcinoma cell lines (11Multhoff G. Botzler C. Jenner L. Schmidt J. Ellwart J. Issels R. J. Immunol. 1997; 158: 4341-4350PubMed Google Scholar, 12Botzler C. Li G. Issels R.D. Multhoff G. Cell Stress Chaperones. 1998; 3: 6-11Crossref PubMed Scopus (112) Google Scholar). The absence of extracellular ATP, however, likely renders the hsp70 chaperone function inoperative. Exogenous hsp70 has recently been shown to elicit a cytokine response after binding to the plasma membrane of monocytes (13Asea A. Kraeft S.-K. Kurt-Jones E.A. Stevenson M.A. Chen L.B. Finberg R.W. Koo G.C. Calderwood S.K. Nat. Med. 2000; 6: 435-442Crossref PubMed Scopus (1344) Google Scholar) and to bind to the surface of antigen-presenting cells and undergo receptor-mediated endocytosis (14Arnold-Schild D. Hanau D. Spehner D. Schmid C. Rammensee H.-G. de la Salle H. Schild H. J. Immunol. 1999; 162: 3757-3760PubMed Google Scholar), consistent with a cell surface “receptor” for hsp70. We have previously described a novel function of hsp70 family members as cell surface-associated, SGL-specific adhesins. Anti-hsp70 antibodies prevent the attachment of mycoplasma (15Boulanger J. Faulds D. Eddy E.M. Lingwood C.A. J. Cell. Physiol. 1995; 165: 7-17Crossref PubMed Scopus (79) Google Scholar), acid-stressed Helicobacter pylori (16Huesca M. Borgia S. Hoffman P. Lingwood C.A. Infect. Immun. 1996; 64: 2643-2648Crossref PubMed Google Scholar), and temperature-stressed Hemophilus influenzae (17Hartmann E. Lingwood C.A. Infect. Immun. 1997; 65: 1729-1733Crossref PubMed Google Scholar) to SGC.1 This SGL binding specificity was found to be shared by the bovine brain hsp70, recombinant mycoplasma hsp70s (15Boulanger J. Faulds D. Eddy E.M. Lingwood C.A. J. Cell. Physiol. 1995; 165: 7-17Crossref PubMed Scopus (79) Google Scholar), and the recombinant testis-specific hsc70 (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar). We have recently extended this survey to demonstrate that recombinant hsp70 family members from Chlamydia trachomatis (6Raulston J.E. Davis C.H. Schmiel D.H. Morgan M.W. Wyrick P.B. J. Biol. Chem. 1993; 268: 23139-23147Abstract Full Text PDF PubMed Google Scholar),H. pylori (19Huesca M. Goodwin A. Bhagwansingh A. Hoffman P. Lingwood C.A. Infect. Immun. 1998; 66: 4061-4067Crossref PubMed Google Scholar), H. influenzae (17Hartmann E. Lingwood C.A. Infect. Immun. 1997; 65: 1729-1733Crossref PubMed Google Scholar),Escherichia coli (20Gassler C.S. Buchberger A. Laufen T. Mayer M.P. Shhroder H. Valencia A. Bukau B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15229-15234Crossref PubMed Scopus (148) Google Scholar), and an hsp70-related extracellular domain from the egg receptor of the sea urchin,Strongylocentrotus purpuratus (21Foltz K.R. Partin J.S. Lennarz W.J. Science. 1993; 259: 1421-1425Crossref PubMed Scopus (150) Google Scholar), all possess the same restricted “lectin” binding specificity for SGC and SGG in vitro. 2Mamelak, D., Mylvaganam, M., Whetstone, H., Hartmann, E., Lennarz, W., Wyrick, P., Raulston, J., Han, H., Hoffman, P., and Lingwood, C. (2001) Biochemistry, in press.2Mamelak, D., Mylvaganam, M., Whetstone, H., Hartmann, E., Lennarz, W., Wyrick, P., Raulston, J., Han, H., Hoffman, P., and Lingwood, C. (2001) Biochemistry, in press. We further found that heterogeneity within the lipid moiety of SGC can differentially modulate binding by prokaryote, as compared with eukaryote, hsp70s, which may reflect their different in vivo adhesin functions. Sulfogalactolipids are found in a variety of tissues and blood cells. SGC is the major sulfoglycolipid of the kidney (23Lingwood C. Hay G. Schachter H. Can. J. Biochem. 1981; 59: 556-563Crossref PubMed Scopus (18) Google Scholar), brain, gastrointestinal tract (24Natomi H. Saitoh T. Sugano K. Iwamori M. Fukayama M. Nagai Y. Lipids. 1993; 28: 737-742Crossref PubMed Scopus (48) Google Scholar, 25Natomi H. Sugano K. Iwamori M. Takaku F. Nagai Y. Biochim. Biophys. Acta. 1988; 961: 213-222Crossref PubMed Scopus (24) Google Scholar), and endometrium (26Kubushiro K. Mikami M. Nozawa S. Ishizuka R. Iwamori M. Nagai Y. Arch. Biochem. Biophys. 1989; 268: 129-136Crossref PubMed Scopus (43) Google Scholar). SGG (with or without SGC) is the major glycolipid of mammalian male germ cells (27Murray R.K. Narasimhan R. Levine M. Pinteric L. Shirley M. Lingwood C.A. Schachter H. Sweeley C. Cell Surface Glycolipids. 128. American Chemical Society, Washington, D. C.1980: 105-125Google Scholar) and has, together with an SGG-binding protein (28Lingwood C.A. Can. J. Biochem. Cell Biol. 1985; 63: 1077-1085Crossref PubMed Scopus (32) Google Scholar, 29Law H. Itkonnen O. Lingwood C.A. J. Cell. Physiol. 1988; 137: 462-468Crossref PubMed Scopus (34) Google Scholar, 30Lingwood C.A. Nutikka A. J. Cell. Physiol. 1991; 146: 258-263Crossref PubMed Scopus (12) Google Scholar) subsequently identified as the testes-specific hsc70 (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar), been implicated in sperm/egg binding (31Tanphaichitr N. Tayabali A. Gradil C. Juneja S. Leveille M.C. Lingwood C.A. Mol. Reprod. Dev. 1992; 32: 17-22Crossref PubMed Scopus (26) Google Scholar, 32Tanphaichitr N. Smith J. Mongkolsirikieart S. Gradil C. Lingwood C.A. Dev. Biol. 1993; 156: 164-175Crossref PubMed Scopus (63) Google Scholar). SGC alone is found in the male germ cells of lower vertebrates (33Levine M. Bain J. Narashinham R. Palmer A. Yates J. Murray R.K. Biochim. Biophys. Acta. 1976; 441: 134-145Crossref PubMed Scopus (27) Google Scholar) and in red and white blood cells (34Ishizuka I. Prog. Lipid Res. 1997; 36: 245-319Crossref PubMed Scopus (218) Google Scholar). Low levels of SGG are found in the mammalian brain (35Ishizuka I. Inomata M. Ueno K. Yamakawa T. J. Biol. Chem. 1978; 253: 898-907Abstract Full Text PDF PubMed Google Scholar), where SGC and SGG synthesis are associated with myelination (36Burkart T. Hofmann K. Siegrist H.P. Herschkowitz N.N. Wiesmann U.N. Dev. Biol. 1981; 83: 42-48Crossref PubMed Scopus (18) Google Scholar). The correlation between SGL localization throughout the body, the tissue tropism of the bacterial pathogens, and the data suggesting that surface-associated hsp70 family members function as SGL-specific adhesins, indicate that hsp70-mediated SGL binding plays a physiological role in, and germ cell binding. the of SGL recognition by hsp70, have the recombinant testes-specific as (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar). The of recombinant products of and site-directed identified a within the conserved N-terminal ATPase critical for SGL binding. The localization of the is considered within the of both the chaperone and adhesin functions of The was and recombinant was and as described previously (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar). The and of the hsp70 family from C. trachomatis was recently and were from all and were from and protein were from and and were from site-directed was from affinity was The was from for and and a for were the of the for of and was the from the was the of was to TLC were from were for were from The was from SGG was from bovine C.A. Murray R.K. Schachter H. J. Immunol. Google Scholar). were from bovine brain, and were from kidney A. H. Lingwood C.A. 1992; PubMed Scopus Google Scholar). and were from protein assay was from of was from a with and a of with was after the and The the was from the and were and for chain reaction was to the of the ATPase domain and further the C-terminal to the substrate-binding domain of was also The terminus of this was to with the C terminus of the ATPase with for and the and were in the chain reaction was the recombinant the as the (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar). The was with the a for by an of for by for and for The to for by for and for The and is to the that the was was as the polymerase for these polymerase was to the reaction after polymerase chain reaction for with no products to fragments of and base and were of E. coli with of from were on and was and with and and the were of the recombinant and of E. coli these were on analysis of the of recombinant with of of E. coli the recombinant were with and to an of the products was the of a were and were with The was to a affinity and with to the recombinant proteins with protein were The and were generated by the site-directed for and The were to the a a for was to the and was by the described by PubMed Scopus Google Scholar). the and was by with for the and of the N-terminal ATPase The was by with a base from the the and of was as described were on Nature. PubMed Scopus Google Scholar). proteins were by with proteins were to and with in for were with the in The in was with the for was with (28Lingwood C.A. Can. J. Biochem. Cell Biol. 1985; 63: 1077-1085Crossref PubMed Scopus (32) Google Scholar). were on a of of was The were and the was with to the of the were in a of and for with and for P. L. K. P. Ishizuka I. S. L. Biochem. J. 1988; 17-22Crossref PubMed Scopus Google Scholar). the were with bovine in and for The was and protein in was to the a the were with saline to in for The were as and with in bovine for a were and protein was by with were were and the of the from binding was of all were in were in to the of and to The were with bovine in for was in the and as a of between the proteins and the of the has been that proteins can bind which is by the of the with C recombinant protein with or without was to the and for with bovine in in was in and for The were with and in was for a the were with in was to the in The were with and to for in the binding was by the of in a a of for the were as the of protein to the were with to prevent were the RELISA is an because of the of this be analysis was to the binding where The polymerase chain reaction was to the N-terminal ATPase of and C-terminal in products were and analysis the base and the and The of and site-directed protein were by of the protein products to and with with all a major in and polymerase chain reaction and polymerase chain reaction of to the the of the in the and in the acid are in The to the the of the in the and in the are in in a The conserved N-terminal of the the and SGG by TLC overlay or RELISA the recombinant N-terminal domain the SGL binding specificity of (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar), because no binding was to the of SGC or or and with not the of to bind The C-terminal of showed no binding to or glycolipid and These demonstrate that the SGL binding of is from the domain Biochim. Biophys. Acta. 1995; PubMed Scopus Google Scholar) and is only within the conserved N-terminal ATPase domain of binding specificity of and the and C-terminal and rP43 SGC and SGG but not the with not binding to the C-terminal substrate-binding domain of showed no binding to glycolipid was a of The recombinant protein products and rP22 further from the rP43 C terminus were compared for binding by TLC overlay to the The binding of rP35 to SGC was compared with and and rP35 SGG in to of SGG by rP29 and the recombinant was severely SGC binding was for the rP29 and for the recombinant The and rP22 were found to bind to but not to lipid The of and to bind of SGC and SGG was also compared by RELISA binding to SGC or SGG was for and binding was for and rP43 to both The binding of and rP22 to both SGC and SGG was not the lipid and The of with the The SGL binding of was not to SGC and SGG in a to the hsp70 from C. for which binding was on The binding of and was for binding to was by analysis as of SGC binding was and SGG binding was SGC binding was by and SGG binding was by of to of SGG and of SGC be binding was only of of to SGC was only SGG binding was only showed a response for binding SGC and SGG by RELISA binding was to The recombinant C-terminal substrate-binding domain showed no binding to of or the showed of SGL binding to the and showed SGL binding by RELISA. of binding was by and for and and for to The binding as by the of the binding was by and for and and for The SGC to the binding of was to be for and for The Phe198 and Arg342 are conserved all the hsp70 family members that have shown to possess SGL binding activity The hsp70 from C. trachomatis is the only to possess a an The of the and the for SGL binding to from the of the terminus of the ATPase C. McKay D.B. Nature. 1990; PubMed Scopus Google Scholar) are shown in B. Arg342 and Phe198 are in and to the Arg342 is from the and Phe198 is from The across the of the ATPase is also the base of this but on the of the and and the with the of this hsp70 family members have recently been described to possess a novel function to SGL (15Boulanger J. Faulds D. Eddy E.M. Lingwood C.A. J. Cell. Physiol. 1995; 165: 7-17Crossref PubMed Scopus (79) Google Scholar, M. Borgia S. Hoffman P. Lingwood C.A. Infect. Immun. 1996; 64: 2643-2648Crossref PubMed Google Scholar, E. Lingwood C.A. Infect. Immun. 1997; 65: 1729-1733Crossref PubMed Google The a to the of The of deletion identified an the C terminus of the N-terminal ATPase domain of critical for SGL binding. within this identified to be for SGC binding by TLC the binding to both SGC and SGG of to not the of SGL binding. a found that an N-terminal of to an SGC a C-terminal not (18Mamelak D. Lingwood C. Glycoconj. J. 1997; 14: 715-722Crossref PubMed Scopus (28) Google Scholar). and further the the of C-terminal deletion within the ATPase domain on SGL binding. TLC overlay and RELISA showed that the is contained only within the N-terminal ATPase the to bind the C-terminal the substrate-binding showed no glycolipid binding. hsp70 has no to the domain in the and extracellular proteins Chem. Lipids. PubMed Scopus Google Scholar, J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, S. R. E. K. D. Res. Hum. 1993; PubMed Scopus Google Scholar). The localization of the from that of residues Biochim. Biophys. Acta. 1995; PubMed Scopus Google Scholar), consistent with that no on SGL binding. TLC SGL binding was for and was for to and further for This binding is not a of because the showed to TLC the glycolipid RELISA a of the cell membrane B. G. Lingwood C.A. J. Biochem. 1994; PubMed Scopus Google Scholar) and a analysis of SGL binding. as by that by TLC overlay because and rP43 SGC and and the C-terminal substrate-binding domain no SGL binding was for the rP29 and rP22 in to TLC RELISA showed that the rP35 SGL binding. rP35 SGL by TLC overlay but not by RELISA. This that major of the high affinity are contained within an from the This the of the C. McKay D.B. Nature. 1990; PubMed Scopus Google Scholar). or a of the recognition domain J. Biophys. 1995; PubMed Scopus Google Scholar) be within the between rP35 and The and rP22 binding in the TLC overlay in the RELISA. the TLC glycolipid is with the with the associated with the and the the may be in a for binding. with to overlay is to the the to facilitate with an N. PubMed Scopus Google Scholar). the is physiological because of the in the the glycolipid to a the of a membrane this that SGL binding by rP35 can SGL and in the of a because of the of an domain the truncation of rP43 to an may in the TLC overlay because the binding of rP35 that of or rP43 by this compared with and rP29 and rP22 showed SGL binding, but only by TLC suggesting that of the are contained in these fragments and can only bind the SGL in the TLC The of a in the deletion may also the binding by and rP22 to recognition of SGC and SGG different but binding on the the recognition from an of lipid of SGC and SGG on the of C.A. Glycoconj. J. 1996; PubMed Scopus Google Scholar). We have recently shown that of SGC binding by different hsp70 family and that the lipid of SGL binding of hsp70 to different of M. Mylvaganam, M. E. H. H. and C. Lingwood, for The lipid moiety can modulate a glycolipid is recognized in the TLC overlay or RELISA B. G. Lingwood C.A. J. Biochem. 1994; PubMed Scopus Google Scholar). SGC and SGG only in the lipid to which the is the hsp70 recognition of SGG may be that of the of the protein of is in a and by by a acid J. F. Nature. 1985; PubMed Scopus Google Scholar). The same is in the implicated in binding. were in this to further the Phe198 was because of the of residues to in J. Biophys. 1995; PubMed Scopus Google Scholar). Arg342 was because of the to bind has also been implicated in the binding of an E. coli adhesin to SGC Infect. Immun. 1999; PubMed Google Scholar). was because is the only in this that the Chlamydia hsp70 which this is from the hsp70s The Chlamydia hsp70 is the only hsp70 that for SGL binding by TLC suggesting that the the may be different for this hsp70. The not the SGL binding specificity or of but the C. trachomatis hsp70, because SGL binding by TLC overlay was in the absence of is not within the is that to SGL Phe198 and Arg342 are conserved not hsp70 family members Arg342 Phe198 have been implicated in ATP binding or C. McKay D.B. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, C. McKay D.B. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The of SGL binding by and indicate that SGL the by the the with the of which be through of with the of The these residues is to the The binding of both was in both suggesting that the same can be by The of on the of SGG may be for with as by is that the plays a role in SGG binding. is that the has a on SGG compared with SGC) binding as by RELISA the same both SGC and SGG binding, because a of SGC that have is an of both SGC and SGG binding to hsp70. M. Mylvaganam, M. E. H. H. and C. Lingwood, for Whetstone, D. and C. Lingwood, for We however, with that recombinant protein the the from the of the terminus of hsc70 C. McKay D.B. Nature. 1990; PubMed Scopus Google Scholar). that the SGL binding for the of Arg342 and Phe198 in SGL the RELISA showed a in SGL binding by rP43 to the SGL is within the this the base of the ATPase the loss may the of the hsp70 family members possess an ATPase function within a conserved N-terminal domain (5Bukau B. Horwich A.L. Cell. 1998; 92: 351-366Abstract Full Text Full Text PDF PubMed Scopus (2397) Google Scholar). The of ATP is critical for hsp70 to facilitate protein and membrane translocation Nature. 1996; PubMed Scopus Google Scholar). These chaperone functions of hsp70 are also by the Y. J. K. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) as as by the L. H. Buchberger A. Bukau B. J. 1997; 36: PubMed Scopus Google Scholar). The of the domain within the conserved N-terminal ATPase domain the of SGL binding members of the hsp70 SGL binding in this domain of hsp70 has the to chaperone by ATP or the of hsp70 with of hsp70 and which also bind within this (20Gassler C.S. Buchberger A. Laufen T. Mayer M.P. Shhroder H. Valencia A. Bukau B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15229-15234Crossref PubMed Scopus (148) Google Scholar, C. M. M. F. J. Science. 1997; PubMed Scopus Google Scholar). ATP has no on binding not SGL binding has a on ATPase activity in the physiological of SGL binding to intracellular hsp70s has to be on bacterial surface hsp70s (15Boulanger J. Faulds D. Eddy E.M. Lingwood C.A. J. Cell. Physiol. 1995; 165: 7-17Crossref PubMed Scopus (79) Google Scholar, M. Borgia S. Hoffman P. Lingwood C.A. Infect. Immun. 1996; 64: 2643-2648Crossref PubMed Google Scholar, E. Lingwood C.A. Infect. Immun. 1997; 65: 1729-1733Crossref PubMed Google together with the that hsp70 cells to a (13Asea A. Kraeft S.-K. Kurt-Jones E.A. Stevenson M.A. Chen L.B. Finberg R.W. Koo G.C. Calderwood S.K. Nat. Med. 2000; 6: 435-442Crossref PubMed Scopus (1344) Google Scholar), indicate that hsp70 a novel an be mediated by the recognition that have described in this We M. for

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.