Kinetic analysis of amyloid formation in the presence of heparan sulfate: faster unfolding and change of pathway.
A number of human diseases are associated with the conversion of proteins from their native state into well defined fibrillar aggregates, depositing in the extracellular space and generally termed amyloid fibrils. Heparan sulfate (HS), a glycosaminoglycan normally present in the extracellular matrix, has been found to be universally associated with amyloid deposits and to promote amyloid fibril formation by all studied protein systems. We have studied the impact of HS on the amyloidogenesis of human muscle acylphosphatase, monitoring the process with an array of techniques, such as normal and stopped-flow far-UV circular dichroism, thioflavin T fluorescence, static and dynamic light scattering, and atomic force microscopy. The results show that HS accelerates the conversion of the studied protein from the native state into the amyloidogenic, yet monomeric, partially folded state. They also indicate that HS does not simply accelerate the conversion of the resulting partially folded state into amyloid species but splits the process into two distinct pathways occurring in parallel: a very fast phase in which HS interacts with a fraction of protein molecules, causing their rapid aggregation into ThT-positive and beta-sheet containing oligomers, and a slow phase resulting from the normal aggregation of partially folded molecules that cannot interact with HS. The HS-mediated aggregation pathway is severalfold faster than that observed in the absence of HS. Two aggregation phases are generally observed when proteins aggregate in the presence of HS, underlying the importance of a detailed kinetic analysis to fully understand the effect of this glycosaminoglycan on amyloidogenesis.
Motamedi-Shad
Neda
N
Department of Biochemistry, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Monsellier
Elodie
E
Torrassa
Silvia
S
Relini
Annalisa
A
Chiti
Fabrizio
F
D017766:Acid Anhydride Hydrolases / Q000737:chemistry* / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D002942:Circular Dichroism; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013844:Thiazoles / Q000737:chemistry*; D000097024:Acylphosphatase
D017766:Acid Anhydride Hydrolases; D000682:Amyloid; D052160:Benzothiazoles; D006497:Heparan Sulfate; D009124:Muscle Proteins; D013844:Thiazoles; D000097024:Acylphosphatase; C009462:thioflavin T
Kidney Int. 2003 Sep;64(3):1080-8
12911560
Biochemistry. 1996 May 21;35(20):6470-82
8639594
Protein Sci. 2006 Apr;15(4):862-70
16600970
Scand J Immunol. 1991 Jul;34(1):63-9
2068532
Protein Sci. 2001 Apr;10(4):879-86
11274479
FEBS Lett. 1998 Dec 18;441(2):271-4
9883898
Am J Pathol. 1988 Dec;133(3):456-63
2974240
Biochemistry. 2000 Aug 1;39(30):8735-46
10913285
Nature. 1997 Feb 27;385(6619):787-93
9039909
J Mol Biol. 2004 Feb 6;336(1):253-62
14741220
J Pathol. 2003 Jul;200(4):423-8
12845610
Protein Expr Purif. 1995 Dec;6(6):799-805
8746632
EMBO J. 2001 Feb 1;20(3):377-86
11157745
Lab Invest. 1990 Nov;63(5):601-11
1977959
Biochemistry. 2007 Oct 30;46(43):12091-9
17924651
J Biol Chem. 1993 Sep 25;268(27):20606-12
8376413
Nat Struct Biol. 1999 Apr;6(4):380-7
10201408
Biochem J. 1988 Dec 15;256(3):775-83
3223951
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3590-4
10097081
J Biol Chem. 2001 Oct 5;276(40):37149-54
11479314
Nat Chem Biol. 2009 Jan;5(1):15-22
19088715
Lab Invest. 1995 Aug;73(2):183-9
7637318
Acta Neuropathol. 1989;78(2):202-9
2473595
Eur J Biochem. 1999 Dec;266(3):1101-10
10583407
Biochemistry. 2006 Feb 21;45(7):2234-42
16475811
J Biol Chem. 2002 Jul 26;277(30):27240-6
12023282
Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16419-26
12374855
Nat Struct Biol. 2002 Feb;9(2):137-43
11799398
Protein Sci. 2005 Jan;14(1):1-12
15576561
J Mol Biol. 1998 Nov 6;283(4):883-91
9790846
Cell. 2005 Apr 8;121(1):73-85
15820680
J Mol Med (Berl). 2003 Nov;81(11):678-99
12942175
J Mol Biol. 1992 Mar 20;224(2):427-40
1313885
Biophys J. 2005 Dec;89(6):4201-10
16169975
Annu Rev Biochem. 2006;75:333-66
16756495
Protein Sci. 1999 Mar;8(3):509-17
10091653
J Mol Biol. 2003 Jul 25;330(5):943-54
12860118
Cell Mol Life Sci. 1997 Feb;53(2):141-51
9118002
Biochemistry. 2003 Dec 30;42(51):15078-83
14690417
Diabetes. 1998 Apr;47(4):612-20
9568695
Arch Pathol Lab Med. 1992 Sep;116(9):951-4
1524461
Biochemistry. 2002 Feb 5;41(5):1502-11
11814343
Lab Invest. 1987 Jun;56(6):665-75
3599910
Nature. 2003 Aug 14;424(6950):805-8
12917692
Biochemistry. 2006 Oct 24;45(42):12806-15
17042499
Mol Cell Neurosci. 2000 Feb;15(2):183-98
10673326
Nature. 1996 Oct 10;383(6600):550-3
8849730
EMBO J. 2000 Apr 3;19(7):1441-9
10747012