Unstructured conformations are a substrate requirement for the Sir2 family of NAD-dependent protein deacetylases

被引:38
作者
Khan, AN [1 ]
Lewis, PN [1 ]
机构
[1] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada
关键词
D O I
10.1074/jbc.M508247200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The regulation of protein function is often achieved through post-translational modifications including phosphorylation, methylation, ubiquitination, and acetylation. The role of acetylation has been most extensively studied in the context of histones, but it is becoming increasingly evident that this modification now includes other proteins. The Sir2 family of NAD-dependent deacetylases was initially recognized as mediating gene silencing through histone deacetylation, but several family members display non-nuclear subcellular localization and deacetylate non-histone protein substrates. Although many structural and enzymatic studies of Sir2 proteins have been reported, how substrate recognition is achieved by this family of enzymes is unknown. Here we use in vitro deacetylase assays and a variety of potential substrates to examine the substrate specificity of yeast homologue Hst2. We show that Hst2 is specific for acetyl-lysine within proteins; it does not deacetylate small polycations such as acetyl-spermine or acetylated amino termini of proteins. Furthermore we have found that Hst2 displays conformational rather than sequence specificity, preferentially deacetylating acetyl-lysine within unstructured regions of proteins. Our results suggest that this conformational requirement may be a general feature for substrate recognition in the Sir2 family.
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收藏
页码:36073 / 36078
页数:6
相关论文
共 29 条
[1]   Structure of a Sir2 enzyme bound to an acetylated p53 peptide [J].
Avalos, JL ;
Celic, I ;
Muhammad, S ;
Cosgrove, MS ;
Boeke, JD ;
Wolberger, C .
MOLECULAR CELL, 2002, 10 (03) :523-535
[2]   Solution structure of oxidized horse heart cytochrome c [J].
Banci, L ;
Bertini, I ;
Gray, HB ;
Luchinat, C ;
Reddig, T ;
Rosato, A ;
Turano, P .
BIOCHEMISTRY, 1997, 36 (32) :9867-9877
[3]   The Sir2 family of protein deacetylases [J].
Blander, G ;
Guarente, L .
ANNUAL REVIEW OF BIOCHEMISTRY, 2004, 73 :417-435
[4]   SIRT1 shows no substrate specificity in vitro [J].
Blander, G ;
Olejnik, J ;
Olejnik, EK ;
Mcdonagh, T ;
Haigis, M ;
Yaffe, MB ;
Guarente, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (11) :9780-9785
[5]   Locus specificity determinants in the multifunctional yeast silencing protein Sir2 [J].
Cuperus, G ;
Shafaatian, F ;
Shore, D .
EMBO JOURNAL, 2000, 19 (11) :2641-2651
[6]   Structural features of helical antimicrobial peptides: their potential to modulate activity on model membranes and biological cells [J].
Dathe, M ;
Wieprecht, T .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1999, 1462 (1-2) :71-87
[7]   Intrinsically unstructured proteins and their functions [J].
Dyson, HJ ;
Wright, PE .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2005, 6 (03) :197-208
[8]  
GU W, 2004, NOVART FDN SYMP, V259, P223
[9]  
Gu Wei, 2004, Novartis Found Symp, V259, P197
[10]   The importance of intrinsic disorder for protein phosphorylation [J].
Iakoucheva, LM ;
Radivojac, P ;
Brown, CJ ;
O'Connor, TR ;
Sikes, JG ;
Obradovic, Z ;
Dunker, AK .
NUCLEIC ACIDS RESEARCH, 2004, 32 (03) :1037-1049