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Structural Basis for Substrate Activation and Regulation by Cystathionine Beta-Synthase (CBS) Domains in Cystathionine Β-Synthase

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Structural Basis for Substrate Activation and Regulation by Cystathionine Beta-Synthase (CBS) Domains in Cystathionine Β-Synthase Corrections BIOCHEMISTRY Correction for “Structural basis for substrate activation and December 7, 2010, of Proc Natl Acad Sci USA (107:20958–20963; regulation by cystathionine beta-synthase (CBS) domains in first published November 16, 2010; 10.1073/pnas.1011448107). cystathionine β-synthase,” by Markos Koutmos, Omer Kabil, The authors note that Figure 3 appeared incorrectly. The cor- Janet L. Smith, and Ruma Banerjee, which appeared in issue 49, rected Figure 3 and its legend appear below. O O H S O H S O 318 318 S N 116 N H - - OOC S116 OOC H O H H HO N O N H C H 2 H CH Y O H CH2 Y O 2 277 277 O HO O O NH2 P P K88 NH O OH 2 O OH K88 external aldimine aminoacrylate intermediate [2] -H2O O O O H S318 S318 O O H S318 S O S S 116 N 116 NH 116 N H - H -OOC H -OOC O OOC H O H O H HO N HO N HO N H H H CH Y277 O H3N CH2 Y277 O H3N CH2 Y277 O H3N 2 O K O K88 O K88 O O 88 O P P P OH OH O OH O O Quinonoid species Carbanion intermediate [1] Fig. 3. Scheme depicting the chemical structures of intermediates in the CBS-catalyzed reaction. www.pnas.org/cgi/doi/10.1073/pnas.1102185108 MICROBIOLOGY CELL BIOLOGY Correction for “Strain-resolved community genomic analysis of Correction for “Unique characteristics of Ca2+ homeostasis of gut microbial colonization in a premature infant,” by Michael J. the trans-Golgi compartment,” by Valentina Lissandron, Paola Morowitz, Vincent J. Denef, Elizabeth K. Costello, Brian C. Podini, Paola Pizzo, and Tullio Pozzan, which appeared in issue Thomas, Valeriy Poroyko, David A. Relman, and Jillian F. Ban- 20, May 18, 2010, of Proc Natl Acad Sci USA (107:9198–9203; field, which appeared in issue 3, January 18, 2011, of Proc Natl first published May 3, 2010; 10.1073/pnas.1004702107). Acad Sci USA (108:1128–1133; first published December 29, The authors note that Paola Podini’saffiliation should instead 2010; 10.1073/pnas.1010992108). appear as “Vita-Salute San Raffaele University and Scientific The authors note that the data deposition footnote should Institute San Raffaele, 20132 Milan, Italy.” The corrected affil- instead appear as “Data deposition: The sequences reported in iation line appears below. The article has been updated online. this paper have been deposited in the Sequence Read Archive (accession nos. SRA026959 and SRA026752) and as a Whole aDepartment of Biomedical Sciences, University of Padua, 35121 Padua, Italy; bVita-Salute San Raffaele University and Scientific Institute San Raffaele, Genome Shotgun project at DDBJ/EMBL/GenBank under the 20132 Milan, Italy; cConsiglio Nazionale delle Ricerche Institute of accession no. AEQT00000000. The version described in this Neuroscience, 35121 Padua, Italy; and dVenetian Institute of Molecular paper is the first version, AEQT01000000.” Medicine, 35129 Padua, Italy www.pnas.org/cgi/doi/10.1073/pnas.1102689108 www.pnas.org/cgi/doi/10.1073/pnas.1102612108 4512 | PNAS | March 15, 2011 | vol. 108 | no. 11 www.pnas.org Downloaded by guest on September 24, 2021 Structural basis for substrate activation and regulation by cystathionine beta-synthase (CBS) domains in cystathionine β-synthase Markos Koutmos1, Omer Kabil, Janet L. Smith, and Ruma Banerjee1 Department of Biological Chemistry and the Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-5606 Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved October 12, 2010 (received for review August 4, 2010) The catalytic potential for H2S biogenesis and homocysteine clear- Table 1. Data collection and refinement statistics (molecular ance converge at the active site of cystathionine β-synthase (CBS), a replacement) β pyridoxal phosphate-dependent enzyme. CBS catalyzes -replace- dCBS + dCBS + ment reactions of either serine or cysteine by homocysteine to give Protein dCBS carbanion aminoacrylate cystathionine and water or H2S, respectively. In this study, high- resolution structures of the full-length enzyme from Drosophila Data collection Space group C2221 C2221 C2221 in which a carbanion (1.70 Å) and an aminoacrylate intermediate Cell dimensions (1.55 Å) have been captured are reported. Electrostatic stabilization a, b, c, Å 92.9, 138.2, 75.2 92.9, 137.9, 75.1 93.2, 138.8, 75.1 of the zwitterionic carbanion intermediate is afforded by the close α, β, γ, ° 90.0, 90.0, 90.0 90.0, 90.0, 90.0 90.0, 90.0, 90.0 positioning of an active site lysine residue that is initially used for Resolution (Å) 50-1.80 50-1.70 50-1.55 Schiff base formation in the internal aldimine and later as a general (1.86-1.80) (1.76-1.70) (1.61-1.55) R base. Additional stabilizing interactions between active site resi- sym (%) 8.0 (40.3) 6.3 (48.2) 10.0 (54.6) I∕σI 19.3 (4.0) 16.4 (3.6) 15.4 (2.1) dues and the catalytic intermediates are observed. Furthermore, Completeness (%) 95.9 (72.2) 98.9 (98.1) 93.8 (67.1) “ ” the structure of the regulatory energy-sensing CBS domains, Redundancy 8.0 (5.8) 5.4 (5.3) 6.6 (3.4) named after this protein, suggests a mechanism for allosteric acti- vation by S-adenosylmethionine. Refinement Resolution, Å 50-1.80 50-1.70 50-1.55 crystallography ∣ hydrogen sulfide No. reflections 42,962 52,465 66,337 R ∕R 0 159∕0 192 0 179∕0 203 0 148∕0 188 work free . No. atoms ydrogen sulfide (H2S), the most recently discovered gaso- Protein 3,843 3,868 3,899 Htransmitter (1, 2), is generated by two enzymes in the Ligands 58 65 64 transsulfuration pathway, cystathionine β-synthase (CBS) and Water 471 598 712 γ-cystathionase, via multiple reactions (3). These enzymes play B factors a key role in homocysteine homeostasis, and mutations in CBS Protein 21.4 21.8 15.2 are the single most common cause of hereditary hyperhomocys- Heme 17.7 20.1 13.4 PLP 11.5 18.5 11.7 teinemia (4). Cysteine, the product of the transsulfuration path- Serine/ — 22.5 (Cα; 22,8) 17.5 way, is the limiting reagent for glutathione biosynthesis and aminoacrylate ∼50% of the cysteine in the hepatic glutathione pool is derived Water 30.1 32.5 32.6 via this route (5). Flux through the transsulfuration pathway is rmsd governed in part by the allosteric effector S-adenosylmethionine Bond lengths, Å 0.004 0.011 0.008 (AdoMet), which binds to the C-terminal regulatory domain of Bond angles, ° 0.847 1.277 1.179 Protein Data 2PC2 2PC4 2PC3 human CBS (hCBS) (6). The latter contains a tandem repeat Bank code of “CBS domains” (CBSDs), a secondary structure motif named after this protein and found across all domains of life (7). CBSDs providing insights into the mechanism of allosteric regulation by are postulated to function as energy-sensing modules (6). AdoMet. The catalytic core of CBS is comprised of an N-terminal heme-binding module followed by a pyridoxal phosphate (PLP) Results domain, which houses the active site. The role of the heme in Structure of Full-Length dCBS. The dCBS monomer (residues CBS is enigmatic, and both structural (8) and regulatory (9) func- 7–510) is composed of two modules connected by a long linker tions have been ascribed to it. Changes in the heme coordination (Fig. 1 A and B): The N-terminal module contains the heme- environment are transmitted to the PLP site some 20 Å away and (red) and PLP- (blue) binding domains, and the C-terminal mod- lead to inhibition of CBS activity via a shift from the ketoenamine to the enolimine tautomer of the PLP (10). Although the crystal structure of the catalytic core of hCBS is known (11, 12), the Author contributions: M.K., O.K., and R.B. designed research; M.K. and O.K. performed architecture of the full-length protein is not. In this study, we re- research; M.K., O.K., J.L.S., and R.B. analyzed data; and M.K. and R.B. wrote the paper. port the structures of full-length Drosophila CBS (dCBS) in the The authors declare no conflict of interest. substrate-free form (at 1.80-Å resolution) and in which two reac- This article is a PNAS Direct Submission. tion intermediates, a carbanion (1.70 Å) and an aminoacrylate Data deposition: The crystallographic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3PC2 for the dCBS substrate-free structure, species (1.55 Å), have been captured (Table 1). The structures 3PC3 for the dCBS aminoacrylate structure, and 3PC4 for the dCBS carbanion structure). reveal how the protein stabilizes the reactive intermediates via 1To whom correspondence may be addressed. E-mail: [email protected] or mkoutmos@ coloumbic interactions with active site residues. Furthermore, umich.edu. our structures reveal the juxtaposition of the regulatory CBSDs This article contains supporting information online at www.pnas.org/lookup/suppl/ and the catalytic core in an activated conformation of the protein, doi:10.1073/pnas.1011448107/-/DCSupplemental. 20958–20963 ∣ PNAS ∣ December 7, 2010 ∣ vol. 107 ∣ no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1011448107 monomers. The linker is also involved in dimerization. In the C-terminal module, hydrogen bonds are formed from H372 and H374 in the linker to the backbone carbonyls of S439* and V438* in the partner subunit (CBSD1*) (Fig. S2). The CBSDs dimerize in a head-to-tail fashion (Figs.
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