PMID- 12855696
OWN - NLM
STAT- MEDLINE
DCOM- 20031117
LR  - 20210206
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 39
DP  - 2003 Sep 26
TI  - The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the 
      basis for divergent substrate specificities of the two lysosomal thioesterases, 
      PPT1 and PPT2.
PG  - 37957-64
AB  - Mutations in palmitoyl protein thioesterase-1 (PPT1) have been found to cause the 
      infantile form of neuronal ceroid lipofuscinosis, which is a lysosomal storage 
      disorder characterized by impaired degradation of fatty acid-modified proteins 
      with accumulation of amorphous granular deposits in cortical neurons, leading to 
      mental retardation and death. Palmitoyl protein thioesterase-2 (PPT2) is a second 
      lysosomal hydrolase that shares a 26% identity with PPT1. A previous study had 
      suggested that palmitoyl-CoA was the preferred substrate of PPT2. Furthermore, 
      PPT2 did not hydrolyze palmitate from the several S-palmitoylated protein 
      substrates. Interestingly, PPT2 deficiency in a recent transgenic mouse model is 
      associated with a form of neuronal ceroid lipofuscinosis, suggesting that PPT1 
      and -2 perform non-redundant roles in lysosomal thioester catabolism. In the 
      current paper, we present the crystal structure of PPT2 at a resolution of 2.7 A. 
      Comparisons of the structures of PPT1 and -2 show very similar architectural 
      features; however, conformational differences in helix alpha4 lead to a 
      solvent-exposed lipid-binding groove in PPT1. The limited space between two 
      parallel loops (beta3-alphaA and beta8-alphaF) located immediately above the 
      lipid-binding groove in PPT2 restricts the binding of fatty acids with bulky head 
      groups, and this binding groove is significantly larger in PPT1. This structural 
      difference accounts for the ability of PPT2 to hydrolyze an unbranched structure 
      such as palmitoyl-CoA but not palmitoylcysteine or palmitoylated proteins. 
      Furthermore, differences in fatty acid chain length specificity of PPT1 and -2, 
      also reported here, are explained by the structure and may provide a biochemical 
      basis for their non-redundant roles.
FAU - Calero, Guillermo
AU  - Calero G
AD  - Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New 
      York 14853-1301, USA.
FAU - Gupta, Praveena
AU  - Gupta P
FAU - Nonato, M Cristina
AU  - Nonato MC
FAU - Tandel, Sagun
AU  - Tandel S
FAU - Biehl, Edward R
AU  - Biehl ER
FAU - Hofmann, Sandra L
AU  - Hofmann SL
FAU - Clardy, Jon
AU  - Clardy J
LA  - eng
SI  - PDB/1PJA
GR  - CA59021/CA/NCI NIH HHS/United States
GR  - NS35323/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030710
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Catalysis
MH  - Crystallization
MH  - Humans
MH  - Molecular Sequence Data
MH  - Substrate Specificity
MH  - Thiolester Hydrolases/*chemistry/metabolism
EDAT- 2003/07/12 05:00
MHDA- 2003/12/03 05:00
CRDT- 2003/07/12 05:00
PHST- 2003/07/12 05:00 [pubmed]
PHST- 2003/12/03 05:00 [medline]
PHST- 2003/07/12 05:00 [entrez]
AID - S0021-9258(20)83366-3 [pii]
AID - 10.1074/jbc.M301225200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Sep 26;278(39):37957-64. doi: 10.1074/jbc.M301225200. Epub 2003 
      Jul 10.