title: GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum.
abstract: Glucose-regulated protein 94 is the HSP90-like protein in the lumen of the endoplasmic reticulum and therefore it chaperones secreted and membrane proteins. It has essential functions in development and physiology of multicellular organisms, at least in part because of this unique clientele. GRP94 shares many biochemical features with other HSP90 proteins, in particular its domain structure and ATPase activity, but also displays distinct activities, such as calcium binding, necessitated by the conditions in the endoplasmic reticulum. GRP94's mode of action varies from the general HSP90 theme in the conformational changes induced by nucleotide binding, and in its interactions with co-chaperones, which are very different from known cytosolic co-chaperones. GRP94 is more selective than many of the ER chaperones and the basis for this selectivity remains obscure. Recent development of molecular tools and functional assays has expanded the spectrum of clients that rely on GRP94 activity, but it is still not clear how the chaperone binds them, or what aspect of folding it impacts. These mechanistic questions and the regulation of GRP94 activity by other proteins and by post-translational modification differences pose new questions and present future research avenues. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).
authors.affiliation: Department of Pathology and Lab Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Marzec
authors.forename: Davide
authors.initials: D
authors.lastname: Eletto
authors.forename: Yair
authors.initials: Y
authors.lastname: Argon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D017510:Protein Folding
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; C018551:glucose-regulated proteins
references.citation: Int Immunol. 2006 Jul;18(7):1147-57
references.pmid: 16772370
references.citation: Mol Cell Biochem. 1999 Jan;191(1-2):97-104
references.pmid: 10094397
references.citation: Dev Biol. 2010 Mar 15;339(2):295-306
references.pmid: 20044986
references.citation: PLoS One. 2009 Aug 31;4(8):e6868
references.pmid: 19718440
references.citation: Science. 2004 Oct 15;306(5695):457-61
references.pmid: 15486293
references.citation: J Natl Cancer Inst. 2002 Apr 3;94(7):504-13
references.pmid: 11929951
references.citation: Nat Cell Biol. 2001 Oct;3(10):891-6
references.pmid: 11584270
references.citation: Cell Stress Chaperones. 1998 Jun;3(2):100-8
references.pmid: 9672245
references.citation: Annu Rev Biochem. 2006;75:271-94
references.pmid: 16756493
references.citation: EMBO J. 2002 Mar 1;21(5):898-908
references.pmid: 11867518
references.citation: Cell Struct Funct. 1995 Feb;20(1):33-9
references.pmid: 7796466
references.citation: J Immunol. 1999 Oct 1;163(7):3842-50
references.pmid: 10490983
references.citation: J Cell Biol. 2010 Jan 25;188(2):223-35
references.pmid: 20100910
references.citation: J Cell Sci. 1998 Sep;111 ( Pt 17):2665-79
references.pmid: 9701565
references.citation: Nat Immunol. 2003 Apr;4(4):321-9
references.pmid: 12612580
references.citation: Cell. 2006 Oct 20;127(2):251-3
references.pmid: 17055424
references.citation: J Biol Chem. 1995 Nov 17;270(46):27589-94
references.pmid: 7499221
references.citation: J Biol Chem. 2003 Nov 28;278(48):48330-8
references.pmid: 12970348
references.citation: J Biol Chem. 1995 Mar 17;270(11):6381-8
references.pmid: 7890776
references.citation: J Mol Evol. 2003 Oct;57(4):408-19
references.pmid: 14708574
references.citation: Biochemistry. 1996 Dec 24;35(51):16760-9
references.pmid: 8988013
references.citation: Mol Cell. 2005 Sep 16;19(6):741-51
references.pmid: 16168370
references.citation: J Biol Chem. 2008 Jun 13;283(24):16446-54
references.pmid: 18417469
references.citation: J Cell Physiol. 1981 Jan;106(1):119-25
references.pmid: 7204505
references.citation: J Biol Chem. 2006 Apr 21;281(16):11301-11
references.pmid: 16461354
references.citation: Mol Cell. 2005 May 27;18(5):601-7
references.pmid: 15916966
references.citation: J Cell Sci. 1986 Dec;86:217-32
references.pmid: 3308928
references.citation: J Virol. 2008 Jun;82(11):5368-80
references.pmid: 18385250
references.citation: Science. 2000 Apr 14;288(5464):331-3
references.pmid: 10764645
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16101-6
references.pmid: 20736353
references.citation: Cell. 1987 Mar 13;48(5):899-907
references.pmid: 3545499
references.citation: Gene Expr. 2010;15(2):75-87
references.pmid: 21526718
references.citation: PLoS One. 2011 Feb 15;6(2):e17109
references.pmid: 21358806
references.citation: J Biol Chem. 1997 Jan 3;272(1):657-62
references.pmid: 8995309
references.citation: EMBO J. 1995 Jul 17;14(14):3425-33
references.pmid: 7628443
references.citation: Science. 1992 Sep 11;257(5076):1496-502
references.pmid: 1523409
references.citation: Mol Cell. 2005 Sep 16;19(6):765-75
references.pmid: 16168372
references.citation: Mol Cell. 2007 Oct 12;28(1):41-56
references.pmid: 17936703
references.citation: J Biol Chem. 2001 Aug 31;276(35):32822-7
references.pmid: 11438552
references.citation: Mol Cancer Ther. 2010 Apr;9(4):942-52
references.pmid: 20371724
references.citation: J Immunol. 2006 Aug 1;177(3):1772-9
references.pmid: 16849487
references.citation: Science. 1995 Sep 15;269(5230):1585-8
references.pmid: 7545313
references.citation: J Biol Chem. 2007 Dec 7;282(49):35612-20
references.pmid: 17925398
references.citation: Mol Cancer Ther. 2006 May;5(5):1256-64
references.pmid: 16731758
references.citation: J Biol Chem. 1987 Sep 15;262(26):12801-5
references.pmid: 3114264
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11600-5
references.pmid: 19553200
references.citation: J Biol Chem. 2009 Mar 20;284(12):7436-45
references.pmid: 19158084
references.citation: Mol Cell Biol. 2003 Nov;23(21):7448-59
references.pmid: 14559994
references.citation: Am J Physiol. 1986 Jan;250(1 Pt 1):C1-17
references.pmid: 3510555
references.citation: Nature. 1996 Jun 13;381(6583):571-9
references.pmid: 8637592
references.citation: Nature. 1997 Mar 27;386(6623):414-7
references.pmid: 9121560
references.citation: Immunity. 2007 Feb;26(2):215-26
references.pmid: 17275357
references.citation: Q Rev Biophys. 2011 May;44(2):229-55
references.pmid: 21414251
references.citation: Nat Immunol. 2000 Aug;1(2):151-5
references.pmid: 11248808
references.citation: Mol Biol Cell. 2009 Mar;20(6):1855-64
references.pmid: 19158397
references.citation: Proc Natl Acad Sci U S A. 1986 May;83(10):3407-11
references.pmid: 3458189
references.citation: Nature. 1996 Dec 5;384(6608):432-8
references.pmid: 8945469
references.citation: J Biol Chem. 2002 Oct 25;277(43):40742-50
references.pmid: 12189140
references.citation: EMBO J. 1998 Aug 17;17(16):4829-36
references.pmid: 9707442
references.citation: EMBO J. 2003 Nov 17;22(22):6127-36
references.pmid: 14609958
references.citation: J Biol Chem. 2004 Apr 16;279(16):16543-52
references.pmid: 14754890
references.citation: Mol Cell. 2007 Jan 12;25(1):151-9
references.pmid: 17218278
references.citation: Science. 2009 Aug 14;325(5942):834-40
references.pmid: 19608861
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12889-94
references.pmid: 14561893
references.citation: J Biol Chem. 2002 Dec 13;277(50):49047-54
references.pmid: 12374812
references.citation: Trends Biochem Sci. 2001 Aug;26(8):504-10
references.pmid: 11504627
references.citation: Cell. 2001 Dec 28;107(7):881-91
references.pmid: 11779464
references.citation: EMBO J. 2002 Sep 2;21(17):4458-69
references.pmid: 12198148
references.citation: J Exp Med. 1992 Sep 1;176(3):657-66
references.pmid: 1512535
references.citation: Biochem J. 2000 Dec 15;352 Pt 3:865-74
references.pmid: 11104697
references.citation: Nat Rev Cancer. 2004 Dec;4(12):966-77
references.pmid: 15573118
references.citation: J Biol Chem. 1989 Oct 15;264(29):17494-501
references.pmid: 2793869
references.citation: J Immunol. 2009 Oct 1;183(7):4205-10
references.pmid: 19752220
references.citation: Immunol Rev. 2005 Oct;207:166-83
references.pmid: 16181335
references.citation: Arch Biochem Biophys. 1997 Aug 1;344(1):18-28
references.pmid: 9244377
references.citation: J Biol Chem. 2005 Oct 7;280(40):33792-9
references.pmid: 16087666
references.citation: J Cell Biol. 2001 Jul 23;154(2):267-73
references.pmid: 11470816
references.citation: Blood. 2011 Jun 30;117(26):7136-44
references.pmid: 21576699
references.citation: J Biol Chem. 1994 Feb 25;269(8):5926-31
references.pmid: 8119936
references.citation: J Biosci. 2007 Apr;32(3):517-30
references.pmid: 17536171
references.citation: FEBS Lett. 2005 Jan 3;579(1):105-14
references.pmid: 15620698
references.citation: FEBS Lett. 2005 Jun 6;579(14):3063-8
references.pmid: 15907843
references.citation: Mol Endocrinol. 1999 Sep;13(9):1435-48
references.pmid: 10478836
references.citation: Biochem J. 2000 Jan 1;345 Pt 1:121-8
references.pmid: 10600647
references.citation: J Mol Biol. 2009 May 22;388(5):1033-42
references.pmid: 19361515
references.citation: Nat Struct Mol Biol. 2011 Jan;18(1):61-6
references.pmid: 21170051
references.citation: Cell. 2007 Feb 9;128(3):577-87
references.pmid: 17289575
references.citation: Mol Cell Biol. 1989 May;9(5):2153-62
references.pmid: 2546060
references.citation: Protein Sci. 2006 Jun;15(6):1260-9
references.pmid: 16731965
references.citation: Mol Cell Biol. 2002 Dec;22(24):8506-13
references.pmid: 12446770
references.citation: FEBS Lett. 2007 Jul 31;581(19):3641-51
references.pmid: 17481612
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):242-8
references.pmid: 10655441
references.citation: J Physiol. 2009 Jan 15;587(2):443-60
references.pmid: 19029185
references.citation: Arch Biochem Biophys. 1992 Jul;296(1):129-36
references.pmid: 1318687
references.citation: Genes Cells. 2007 Sep;12(9):1063-73
references.pmid: 17825049
references.citation: J Biol Chem. 2009 Aug 21;284(34):22559-67
references.pmid: 19553666
references.citation: Biochim Biophys Acta. 2009 Feb;1793(2):239-52
references.pmid: 19000718
references.citation: BMC Genomics. 2006 Jun 17;7:156
references.pmid: 16780600
references.citation: Ann Oncol. 2003 Aug;14(8):1169-76
references.pmid: 12881371
references.citation: EMBO J. 1997 Dec 1;16(23):7207-16
references.pmid: 9384597
references.citation: J Biol Chem. 2008 Jul 25;283(30):21170-8
references.pmid: 18492664
references.citation: Nat Struct Biol. 1997 Jun;4(6):477-82
references.pmid: 9187656
references.citation: J Biol Chem. 1987 Jun 25;262(18):8875-83
references.pmid: 3036833
references.citation: FEBS Lett. 1996 Mar 11;382(1-2):149-52
references.pmid: 8612738
references.citation: Mol Cell Biochem. 2011 Oct;356(1-2):191-200
references.pmid: 21739154
references.citation: Protein Sci. 2009 Sep;18(9):1815-27
references.pmid: 19554567
references.citation: Mol Cell. 2008 Mar 14;29(5):541-51
references.pmid: 18342602
references.citation: Nature. 1994 Aug 4;370(6488):373-5
references.pmid: 7913987
references.citation: J Biol Chem. 2007 Jul 6;282(27):19742-52
references.pmid: 17485462
references.citation: J Immunol. 2009 Oct 15;183(8):5121-8
references.pmid: 19786553
references.citation: Curr Opin Cell Biol. 1992 Apr;4(2):267-73
references.pmid: 1599691
references.citation: Biochim Biophys Acta. 2008 Apr;1783(4):549-56
references.pmid: 18191641
references.citation: J Cell Biol. 1990 May;110(5):1501-11
references.pmid: 2335560
references.citation: Mol Biol Cell. 2007 Oct;18(10):3764-75
references.pmid: 17634284
references.citation: Antioxid Redox Signal. 2003 Aug;5(4):381-7
references.pmid: 13678525
references.citation: Blood. 1998 Jun 1;91(11):4379-86
references.pmid: 9596688
references.citation: J Biol Chem. 1997 Oct 17;272(42):26095-102
references.pmid: 9334173
references.citation: J Biol Chem. 1995 Jun 2;270(22):13524-33
references.pmid: 7768954
references.citation: J Biol Chem. 1992 May 25;267(15):10631-7
references.pmid: 1316906
references.citation: Nat Cell Biol. 2008 Mar;10(3):272-82
references.pmid: 18264092
references.citation: Blood. 2008 Aug 15;112(4):1223-30
references.pmid: 18509083
references.citation: J Biol Chem. 2005 Aug 26;280(34):30438-47
references.pmid: 15951571
references.citation: Trends Endocrinol Metab. 2010 Nov;21(11):652-9
references.pmid: 20724178
references.citation: ACS Chem Biol. 2011 Aug 19;6(8):800-7
references.pmid: 21548602
references.citation: Biochemistry. 1998 Apr 21;37(16):5709-19
references.pmid: 9548957
references.citation: Blood. 2010 Mar 25;115(12):2380-90
references.pmid: 19965672
references.citation: Cell Death Differ. 2008 Aug;15(8):1304-17
references.pmid: 18437163
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5578-83
references.pmid: 11331745
references.citation: Biochem Biophys Res Commun. 2007 Aug 3;359(3):778-83
references.pmid: 17560942
references.citation: J Biol Chem. 2002 Jul 12;277(28):25082-9
references.pmid: 11983709
references.citation: Cell. 2007 Mar 23;128(6):1147-59
references.pmid: 17382883
references.citation: Nucleic Acids Res. 1999 Mar 15;27(6):1437-43
references.pmid: 10037803
references.citation: J Biol Chem. 2004 Oct 29;279(44):46162-71
references.pmid: 15292259
references.citation: J Biol Chem. 2004 Apr 23;279(17):18026-33
references.pmid: 14871888
references.citation: J Biol Chem. 2011 Jul 29;286(30):26327-33
references.pmid: 21636579
references.citation: J Biol Chem. 2002 May 31;277(22):19265-75
references.pmid: 11877417
references.citation: J Biol Chem. 1998 Dec 11;273(50):33741-9
references.pmid: 9837962
references.citation: EMBO J. 1995 May 15;14(10):2281-92
references.pmid: 7774586
references.citation: Nat Commun. 2010 Sep 21;1:79
references.pmid: 20865800
references.citation: Immunity. 2003 Feb;18(2):243-53
references.pmid: 12594951
references.citation: J Mol Biol. 1996 Aug 23;261(3):328-33
references.pmid: 8780775
references.citation: Cell Stress Chaperones. 1997 Dec;2(4):252-62
references.pmid: 9495282
references.citation: Dev Cell. 2005 Oct;9(4):545-54
references.pmid: 16198296
references.citation: Curr Top Microbiol Immunol. 1991;167:109-23
references.pmid: 1711433
references.citation: Trends Biochem Sci. 2000 Jan;25(1):24-8
references.pmid: 10637609
references.citation: Eur J Biochem. 2003 Jan;270(1):146-54
references.pmid: 12492485
references.citation: Crit Rev Eukaryot Gene Expr. 1994;4(1):1-18
references.pmid: 7987045
references.citation: Proc Natl Acad Sci U S A. 1977 Sep;74(9):3840-4
references.pmid: 198809
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Immunol Today. 1995 May;16(5):243-50
references.pmid: 7779255
references.citation: Expert Opin Biol Ther. 2007 Nov;7(11):1679-88
references.pmid: 17961091
references.citation: Int J Cancer. 1996 Aug 22;69(4):340-9
references.pmid: 8797880
references.citation: J Nutr. 1990 Nov;120(11):1412-7
references.pmid: 2231029
references.citation: J Biol Chem. 2000 Nov 24;275(47):37181-6
references.pmid: 10945979
references.citation: FEBS Lett. 2000 Apr 14;471(2-3):151-5
references.pmid: 10767412
references.citation: Biochem J. 2007 Jul 15;405(2):233-41
references.pmid: 17411420
references.citation: Mol Endocrinol. 2008 Feb;22(2):477-84
references.pmid: 17916655
references.citation: Adv Cancer Res. 1993;62:153-77
references.pmid: 8109317
references.citation: Curr Opin Immunol. 2006 Apr;18(2):201-5
references.pmid: 16464565
references.citation: J Cell Physiol. 1997 Feb;170(2):115-29
references.pmid: 9009140
references.citation: J Biol Chem. 2009 Jan 23;284(4):2482-92
references.pmid: 19011241
references.citation: J Biol Chem. 2004 Nov 19;279(47):48915-22
references.pmid: 15364938
references.citation: J Biol Chem. 2000 Jul 28;275(30):22806-14
references.pmid: 10816560
references.citation: Eur J Biochem. 1996 Jan 15;235(1-2):18-25
references.pmid: 8631326
references.citation: Int J Mol Med. 2000 Sep;6(3):259-64
references.pmid: 10934286
references.citation: Nat Cell Biol. 2005 Feb;7(2):186-94
references.pmid: 15665855