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Crystal structure of rat liver betaine homocysteine s-methyltransferase reveals new oligomerization features and conformational changes upon substrate binding.

González B, Pajares MA, Martínez-Ripoll M, Blundell TL, Sanz-Aparicio J
J Mol Biol 338 771-82 (2004)
Cited: 24 times
EuropePMC logo PMID: 15099744

Abstract

Betaine homocysteine S-methyltransferase (BHMT) is one of the two enzymes known to methylate homocysteine to generate methionine in the liver. It presents a Zn(2+) atom linked to three essential Cys residues. The crystal structure of rat liver BHMT has been solved at 2.5A resolution, using crystals with P2(1) symmetry and 45% solvent content in the cell. The asymmetric unit contains the whole functional tetramer showing point symmetry 222. The overall fold of the subunit consists mostly of a (alpha/beta)(8) barrel, as for human BHMT. From the end of the barrel, the polypeptide chain extends away and makes many interactions with a different subunit, forming tight dimers. The most remarkable structural feature of rat liver BHMT is the presence of a helix including residues 381-407, at the C terminus of the chain, which bind together the dimers AB to CD. A strong ion-pair and more than 60 hydrophobic interactions keep this helix stacked to the segment 316-349 from the opposite subunit. Moreover, the crystal structure of free rat liver BHMT clearly shows that Tyr160 is the fourth ligand coordinated to Zn, which is replaced by Hcy upon binding. Two residues essential for substrate recognition, Phe76 and Tyr77, are provided by a conformational change in a partially disordered loop (L2). The crucial role of these residues is highlighted by site-directed mutagenesis.

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  5. The correlation of 113Cd NMR and 111mCd PAC spectroscopies provides a powerful approach for the characterization of the structure of Cd(II)-substituted Zn(II) proteins. Iranzo O, Jakusch T, Lee KH, Hemmingsen L, Pecoraro VL. Chemistry 15 3761-3772 (2009)
  6. Autophagic activity measured in whole rat hepatocytes as the accumulation of a novel BHMT fragment (p10), generated in amphisomes by the asparaginyl proteinase, legumain. Øverbye A, Sætre F, Hagen LK, Johansen HT, Seglen PO. Autophagy 7 1011-1027 (2011)
  7. Is protein methylation in the human lens a result of non-enzymatic methylation by S-adenosylmethionine? Truscott RJ, Mizdrak J, Friedrich MG, Hooi MY, Lyons B, Jamie JF, Davies MJ, Wilmarth PA, David LL. Exp Eye Res 99 48-54 (2012)
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  15. Specific potassium ion interactions facilitate homocysteine binding to betaine-homocysteine S-methyltransferase. Mládková J, Hladílková J, Diamond CE, Tryon K, Yamada K, Garrow TA, Jungwirth P, Koutmos M, Jiráček J. Proteins 82 2552-2564 (2014)
  16. Splicing variants of the porcine betaine-homocysteine S-methyltransferase gene: implications for mammalian metabolism. Ganu R, Garrow T, Koutmos M, Rund L, Schook LB. Gene 529 228-237 (2013)
  17. Identification of hepatic protein-protein interaction targets for betaine homocysteine S-methyltransferase. Garrido F, Pacheco M, Vargas-Martínez R, Velasco-García R, Jorge I, Serrano H, Portillo F, Vázquez J, Pajares MÁ. PLoS One 13 e0199472 (2018)
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Related citations provided by authors (2)

  1. Active-site-mutagenesis study of rat liver betaine-homocysteine S-methyltransferase.. González B, Campillo N, Garrido F, Gasset M, Sanz-Aparicio J, Pajares MA Biochem J 370 945-52 (2003)
  2. Crystallization and preliminary X-ray study of recombinant betaine-homocysteine S-methyltransferase from rat liver.. González B, Pajares MA, Too HP, Garrido F, Blundell TL, Sanz-Aparicio J Acta Crystallogr D Biol Crystallogr 58 1507-10 (2002)

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