title: Structural basis of regulation and oligomerization of human cystathionine β-synthase, the central enzyme of transsulfuration.
abstract: Cystathionine β-synthase (CBS) controls the flux of sulfur from methionine to cysteine, a precursor of glutathione, taurine, and H2S. CBS condenses serine and homocysteine to cystathionine with the help of three cofactors, heme, pyridoxal-5'-phosphate, and S-adenosyl-l-methionine. Inherited deficiency of CBS activity causes homocystinuria, the most frequent disorder of sulfur metabolism. We present the structure of the human enzyme, discuss the unique arrangement of the CBS domains in the C-terminal region, and propose how they interact with the catalytic core of the complementary subunit to regulate access to the catalytic site. This arrangement clearly contrasts with other proteins containing the CBS domain including the recent Drosophila melanogaster CBS structure. The absence of large conformational changes and the crystal structure of the partially activated pathogenic D444N mutant suggest that the rotation of CBS motifs and relaxation of loops delineating the entrance to the catalytic site represent the most likely molecular mechanism of CBS activation by S-adenosyl-l-methionine. Moreover, our data suggest how tetramers, the native quaternary structure of the mammalian CBS enzymes, are formed. Because of its central role in transsulfuration, redox status, and H2S biogenesis, CBS represents a very attractive therapeutic target. The availability of the structure will help us understand the pathogenicity of the numerous missense mutations causing inherited homocystinuria and will allow the rational design of compounds modulating CBS activity.
authors.affiliation: Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), 48160 Bizkaia, Spain.
authors.forename: June
authors.initials: J
authors.lastname: Ereño-Orbea
authors.forename: Tomas
authors.initials: T
authors.lastname: Majtan
authors.forename: Iker
authors.initials: I
authors.lastname: Oyenarte
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kraus
authors.forename: Luis Alfonso
authors.initials: LA
authors.lastname: Martínez-Cruz
mesh_terms: D015153:Blotting, Western; D003460:Crystallization; D003541:Cystathionine beta-Synthase / Q000737:chemistry*; D058645:Denaturing Gradient Gel Electrophoresis; D006801:Humans; D008958:Models, Molecular; D058105:Polymerization; D011487:Protein Conformation; D013455:Sulfur / Q000737:chemistry*
chemical_list: D013455:Sulfur; D003541:Cystathionine beta-Synthase
references.citation: J Biol Chem. 2008 Dec 12;283(50):34588-95
references.pmid: 18849566
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
references.pmid: 21460454
references.citation: Biochemistry. 2002 Oct 1;41(39):11832-7
references.pmid: 12269827
references.citation: Trends Biochem Sci. 1997 Jan;22(1):12-3
references.pmid: 9020585
references.citation: Nat Genet. 1998 May;19(1):91-3
references.pmid: 9590298
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references.pmid: 20124692
references.citation: Biochemistry. 1999 Oct 5;38(40):13155-61
references.pmid: 10529187
references.citation: Methods. 2011 Sep;55(1):94-106
references.pmid: 21821126
references.citation: J Am Chem Soc. 2009 Sep 9;131(35):12809-16
references.pmid: 19722721
references.citation: J Mol Biol. 2010 Feb 26;396(3):800-20
references.pmid: 20026078
references.citation: Hum Mutat. 2002 Jun;19(6):641-55
references.pmid: 12007221
references.citation: Nat Rev Drug Discov. 2007 Nov;6(11):917-35
references.pmid: 17948022
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12474-9
references.pmid: 23836652
references.citation: Arch Biochem Biophys. 1998 Jul 15;355(2):222-32
references.pmid: 9675031
references.citation: Biochem J. 2013 Jan 1;449(1):109-21
references.pmid: 22985361
references.citation: J Biol Chem. 2004 Jul 16;279(29):29871-4
references.pmid: 15087459
references.citation: Thromb Haemost. 1997 Jul;78(1):520-2
references.pmid: 9198207
references.citation: Hum Mol Genet. 2001 Mar 15;10(6):635-43
references.pmid: 11230183
references.citation: EMBO J. 2001 Aug 1;20(15):3910-6
references.pmid: 11483494
references.citation: Nat Prod Rep. 2007 Jun;24(3):631-9
references.pmid: 17534535
references.citation: Protein Expr Purif. 2012 Apr;82(2):317-24
references.pmid: 22333527
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: J Mol Biol. 2010 May 28;399(1):53-70
references.pmid: 20382158
references.citation: J Struct Biol. 2013 Jul;183(1):40-6
references.pmid: 23664870
references.citation: J Biol Chem. 2000 Apr 21;275(16):11541-4
references.pmid: 10766767
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Nov 1;68(Pt 11):1318-22
references.pmid: 23143240
references.citation: J Inherit Metab Dis. 2006 Feb;29(1):3-20
references.pmid: 16601863
references.citation: J Biol Chem. 2010 May 21;285(21):15866-73
references.pmid: 20308073
references.citation: Biochemistry. 2001 Sep 4;40(35):10625-33
references.pmid: 11524006
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references.pmid: 20383002
references.citation: ACS Chem Biol. 2011 Nov 18;6(11):1156-63
references.pmid: 21958115
references.citation: Semin Thromb Hemost. 2000;26(3):219-25
references.pmid: 11011839
references.citation: Biochemistry. 2007 Apr 3;46(13):4110-6
references.pmid: 17352495
references.citation: J Inorg Biochem. 2000 Aug 31;81(3):161-71
references.pmid: 11051561
references.citation: Biochemistry. 2002 Aug 20;41(33):10454-61
references.pmid: 12173932
references.citation: J Clin Invest. 1996 Jul 15;98(2):285-9
references.pmid: 8755636
references.citation: Am J Hum Genet. 2001 Jun;68(6):1506-13
references.pmid: 11359213
references.citation: Biochemistry. 2010 Dec 14;49(49):10526-34
references.pmid: 21062078
references.citation: Br J Haematol. 1998 May;101 Suppl 1:18-20
references.pmid: 9607738
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20958-63
references.pmid: 21081698
references.citation: Biochemistry. 2012 Jun 12;51(23):4755-63
references.pmid: 22612060
references.citation: N Engl J Med. 1998 Apr 9;338(15):1042-50
references.pmid: 9535670