Hsp70: Difference between revisions
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==Structure of Hsp70== | ==Structure of Hsp70== | ||
<StructureSection load='5aqh' size='340' side='right';' scene=''> | <StructureSection load='5aqh' size='340' side='right';' scene=''> | ||
Here is a better first view of the molecule <scene name='81/813405/Main_screen/ | Here is a better first view of the molecule <scene name='81/813405/Main_screen/5'>here</scene>. | ||
'''Overview''' | '''Overview''' | ||
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A <scene name='81/813405/Scene_alex_4/1'>proline switch</scene> has been discovered in position 147 of human Hsp70. A study done to understand this mechanism used E. coli’s DnaK which is a homolog of human Hsp70. Proline 143 is the corresponding residue in DnaK for Proline 147 in the ATPase domain. This proline is universally conserved and undertakes alternate conformations in response to ATP binding and hydrolysis. This proline is directly involved in catalytic residue positioning by facilitating the contact between Lys70 (Lys71 in humans)… and/or Glu171 (Glu175 in humans). Changing the Proline to an Alanine or Glycine residue affected Lysine70’s positioning in the catalytic domain. Furthermore, lack of an extra amide hydrogen in proline, as opposed to Alanine and Glycine’s extra hydrogen on their amide group, seems to be beneficial for interaction with the Glutamine171 residue. Both findings show how critical the proline residue is for catalytic domain function because without it the rate of ATP hydrolysis is greatly reduced. The Lys70 and Glu171 are positioned ideally for nucleophilic attack by water to hydrolyze the bound ATP. This process then sends a signal to the SBD to open its pocket which finally allows substrate binding. <ref name="Vogel">Vogel, M., Bukau, B., & Mayer, M. P. (2006). Allosteric Regulation of Hsp70 Chaperones by a Proline Switch. Molecular Cell, 21(3), 359-367. doi:10.1016/j.molcel.2005.12.017</ref> | A <scene name='81/813405/Scene_alex_4/1'>proline switch</scene> has been discovered in position 147 of human Hsp70. A study done to understand this mechanism used E. coli’s DnaK which is a homolog of human Hsp70. Proline 143 is the corresponding residue in DnaK for Proline 147 in the ATPase domain. This proline is universally conserved and undertakes alternate conformations in response to ATP binding and hydrolysis. This proline is directly involved in catalytic residue positioning by facilitating the contact between Lys70 (Lys71 in humans)… and/or Glu171 (Glu175 in humans). Changing the Proline to an Alanine or Glycine residue affected Lysine70’s positioning in the catalytic domain. Furthermore, lack of an extra amide hydrogen in proline, as opposed to Alanine and Glycine’s extra hydrogen on their amide group, seems to be beneficial for interaction with the Glutamine171 residue. Both findings show how critical the proline residue is for catalytic domain function because without it the rate of ATP hydrolysis is greatly reduced. The Lys70 and Glu171 are positioned ideally for nucleophilic attack by water to hydrolyze the bound ATP. This process then sends a signal to the SBD to open its pocket which finally allows substrate binding. <ref name="Vogel">Vogel, M., Bukau, B., & Mayer, M. P. (2006). Allosteric Regulation of Hsp70 Chaperones by a Proline Switch. Molecular Cell, 21(3), 359-367. doi:10.1016/j.molcel.2005.12.017</ref> | ||
An image of the residues in the NBD contact with the ADP can be viewed <scene name='81/813405/Contact_to_adp/ | An image of the residues in the NBD contact with the ADP can be viewed <scene name='81/813405/Contact_to_adp/2'>here</scene>. | ||
ATP is not the only means of allosteric control on this enzyme. When a polypeptide binds to the SBD it actually decreases the stabilization between the SBD and NBD domains. The SBD change caused by polypeptide binding is transmitted to the NBD which increases the rate of ATP Hydrolysis in that domain <ref>Young J. C. (2010). Mechanisms of the Hsp70 chaperone system. Biochemistry and cell biology = Biochimie et biologie cellulaire, 88(2), 291-300</ref>. | ATP is not the only means of allosteric control on this enzyme. When a polypeptide binds to the SBD it actually decreases the stabilization between the SBD and NBD domains. The SBD change caused by polypeptide binding is transmitted to the NBD which increases the rate of ATP Hydrolysis in that domain <ref>Young J. C. (2010). Mechanisms of the Hsp70 chaperone system. Biochemistry and cell biology = Biochimie et biologie cellulaire, 88(2), 291-300</ref>. | ||