title: Altered backbone and side-chain interactions result in route heterogeneity during the folding of interleukin-1β (IL-1β).
abstract: Deletion of the β-bulge trigger-loop results in both a switch in the preferred folding route, from the functional loop packing folding route to barrel closure, as well as conversion of the agonist activity of IL-1β into antagonist activity. Conversely, circular permutations of IL-1β conserve the functional folding route as well as the agonist activity. These two extremes in the folding-functional interplay beg the question of whether mutations in IL-1β would result in changes in the populations of heterogeneous folding routes and the signaling activity. A series of topologically equivalent water-mediated β-strand bridging interactions within the pseudosymmetric β-trefoil fold of IL-1β highlight the backbone water interactions that stabilize the secondary and tertiary structure of the protein. Additionally, conserved aromatic residues lining the central cavity appear to be essential for both stability and folding. Here, we probe these protein backbone-water molecule and side chain-side chain interactions and the role they play in the folding mechanism of this geometrically stressed molecule. We used folding simulations with structure-based models, as well as a series of folding kinetic experiments to examine the effects of the F42W core mutation on the folding landscape of IL-1β. This mutation alters water-mediated backbone interactions essential for maintaining the trefoil fold. Our results clearly indicate that this perturbation in the primary structure alters a structural water interaction and consequently modulates the population of folding routes accessed during folding and signaling activity.
authors: Department of Chemistry and Biochemistry, University of California, La Jolla, CA, USA.
authors: Dominique T
authors: DT
authors: Capraro
authors: Heiko
authors: H
authors: Lammert
authors: David K
authors: DK
authors: Heidary
authors: Melinda
authors: M
authors: Roy
authors: Larry A
authors: LA
authors: Gross
authors: José N
authors: JN
authors: Onuchic
authors: Patricia A
authors: PA
authors: Jennings
mesh_terms: D019943:Amino Acid Substitution; D053583:Interleukin-1beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D055620:Optical Phenomena; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D053583:Interleukin-1beta; D014867:Water
references: J Mol Biol. 1998 Apr 10;277(4):933-43
references: 9545382
references: Proteins. 2005 Aug 15;60(3):450-63
references: 15937899
references: Proteins. 2007 Jun 1;67(4):868-85
references: 17380484
references: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10254-10258
references: 16801558
references: J Mol Biol. 1994 Mar 11;236(5):1369-81
references: 8126726
references: J Mol Biol. 2001 Mar 23;307(2):657-69
references: 11254388
references: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9613-5
references: 10449741
references: Protein Sci. 2008 Apr;17(4):652-63
references: 18305195
references: Biochemistry. 1994 Dec 27;33(51):15250-8
references: 7803387
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W555-62
references: 20478824
references: FEBS Lett. 1990 Mar 12;262(1):20-4
references: 2318308
references: J Mol Biol. 2002 Feb 22;316(3):789-98
references: 11866531
references: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5871-6
references: 10811910
references: J Chem Theory Comput. 2008 Mar;4(3):435-47
references: 26620784
references: Acta Crystallogr D Biol Crystallogr. 2003 Feb;59(Pt 2):290-8
references: 12554939
references: PLoS One. 2013 Apr 12;8(4):e61222
references: 23593437
references: J Mol Biol. 2004 Apr 23;338(2):419-35
references: 15066441
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: J Mol Biol. 2005 Nov 11;353(5):1187-98
references: 16216268
references: Philos Trans R Soc Lond B Biol Sci. 1995 Apr 29;348(1323):35-41
references: 7770484
references: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14844-8
references: 18806223
references: J Mol Biol. 2001 Aug 24;311(4):879-90
references: 11518537
references: Proteins. 1995 Mar;21(3):167-95
references: 7784423
references: Structure. 2009 Aug 12;17(8):1042-50
references: 19679084
references: Proteins. 1992 Jan;12(1):10-23
references: 1553379
references: BMC Bioinformatics. 2007 Nov 22;8:460
references: 18034891
references: Biochemistry. 2000 Jan 25;39(3):575-83
references: 10642182
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W657-61
references: 20525782
references: J Mol Biol. 1989 Oct 20;209(4):779-91
references: 2585509
references: Endocrinology. 1994 Jan;134(1):457-60
references: 8275959
references: J Mol Biol. 2005 Feb 11;346(1):307-18
references: 15663946
references: Proteins. 2009 Dec;77(4):881-91
references: 19626713
references: PLoS One. 2012;7(6):e38512
references: 22693643
references: Am J Reprod Immunol. 2004 Sep;52(3):218-23
references: 15373762
references: J Mol Biol. 2003 Jul 11;330(3):553-70
references: 12842471
references: Biophys J. 1992 Apr;62(1):112-5
references: 1534698
references: J Am Chem Soc. 2004 Jun 30;126(25):7991-8000
references: 15212549
references: Nat Struct Biol. 1997 Sep;4(9):725-31
references: 9303000
references: J Mol Biol. 2006 Mar 31;357(3):986-96
references: 16469330
references: Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1490-3
references: 22307602
references: J Phys Chem B. 2005 Jan 20;109(2):1015-22
references: 16866474
references: Nature. 1997 Mar 13;386(6621):190-4
references: 9062193
references: Biochemistry. 1990 Jun 19;29(24):5671-6
references: 2383553
references: Science. 1993 May 21;260(5111):1110-3
references: 8493553