An unusual hydrophobic core confers extreme flexibility to HEAT repeat proteins.
Alpha-solenoid proteins are suggested to constitute highly flexible macromolecules, whose structural variability and large surface area is instrumental in many important protein-protein binding processes. By equilibrium and nonequilibrium molecular dynamics simulations, we show that importin-beta, an archetypical alpha-solenoid, displays unprecedentedly large and fully reversible elasticity. Our stretching molecular dynamics simulations reveal full elasticity over up to twofold end-to-end extensions compared to its bound state. Despite the absence of any long-range intramolecular contacts, the protein can return to its equilibrium structure to within 3 A backbone RMSD after the release of mechanical stress. We find that this extreme degree of flexibility is based on an unusually flexible hydrophobic core that differs substantially from that of structurally similar but more rigid globular proteins. In that respect, the core of importin-beta resembles molten globules. The elastic behavior is dominated by nonpolar interactions between HEAT repeats, combined with conformational entropic effects. Our results suggest that alpha-solenoid structures such as importin-beta may bridge the molecular gap between completely structured and intrinsically disordered proteins.
Kappel
Christian
C
Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Zachariae
Ulrich
U
Dölker
Nicole
N
Grubmüller
Helmut
H
D020816:Amino Acid Motifs; D004548:Elasticity; D019277:Entropy; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae; D028961:beta Karyopherins / Q000737:chemistry* / Q000378:metabolism
D005656:Fungal Proteins; D028961:beta Karyopherins
J Comput Chem. 2005 Dec;26(16):1701-18
16211538
Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12860-4
15322276
J Mol Biol. 1999 Feb 19;286(2):553-61
9973570
Nature. 2006 Mar 9;440(7081):246-9
16415852
Biochim Biophys Acta. 1995 Dec 6;1253(2):151-62
8519796
J Am Chem Soc. 1988 Mar 1;110(6):1657-66
27557051
Nature. 2004 Dec 2;432(7017):573-9
15502812
J Mol Biol. 2005 Jun 10;349(3):515-25
15878174
Biophys J. 1997 May;72(5):2032-41
9129806
Structure. 2005 Apr;13(4):669-82
15837205
Science. 2003 Nov 28;302(5650):1571-5
14645851
Biophys J. 2010 Apr 7;98(7):1294-301
20371329
J Chem Theory Comput. 2008 Mar;4(3):435-47
26620784
Curr Opin Struct Biol. 2000 Jun;10(3):279-85
10851197
Science. 1996 Feb 16;271(5251):997-9
8584939
J Biol Chem. 2008 Mar 21;283(12):7877-84
18187419
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2467-72
20133745
Curr Opin Struct Biol. 2006 Apr;16(2):237-44
16567089
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7600-5
15133147
J Mol Biol. 2001 May 25;309(1):1-18
11491282
Protein Eng. 2001 Nov;14(11):897-901
11742109
Protein Sci. 1996 Aug;5(8):1584-93
8844848
J Mol Biol. 1999 Oct 22;293(2):321-31
10550212
Nat Methods. 2008 Jun;5(6):491-505
18511917
Nature. 1999 May 20;399(6733):221-9
10353244
Nat Genet. 1995 Oct;11(2):115-6
7550332
Trends Biochem Sci. 2000 Oct;25(10):509-15
11050437
Biophys J. 2009 Feb 18;96(4):1350-63
19217853
Trends Biochem Sci. 1995 Sep;20(9):376-9
7482708
J Mol Biol. 1987 Aug 5;196(3):657-75
3681971
Structure. 2006 Sep;14(9):1469-78
16962977
J Am Chem Soc. 2005 Jul 27;127(29):10188-90
16028928
Nature. 2005 Jun 2;435(7042):693-6
15864302
Prog Biophys Mol Biol. 2009 Feb-Apr;99(2-3):94-103
19344736
Science. 2008 Jun 13;320(5882):1471-5
18556554
Structure. 2009 Sep 9;17(9):1156-68
19748337
Structure. 2008 Jun;16(6):906-15
18547523
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9982-7
18632570
FEBS Lett. 1990 Mar 12;262(1):20-4
2318308
Nat Rev Mol Cell Biol. 2007 Mar;8(3):195-208
17287812
Nature. 2007 Oct 25;449(7165):1063-7
17891154
Structure. 2000 Dec 15;8(12):1319-28
11188696