PMID- 36088080
OWN - NLM
STAT- MEDLINE
DCOM- 20220913
LR  - 20230125
IS  - 1876-1631 (Electronic)
IS  - 1876-1623 (Linking)
VI  - 132
DP  - 2022
TI  - Computational and structural investigation of Palmitoyl-Protein Thioesterase 1 
      (PPT1) protein causing Neuronal Ceroid Lipofuscinoses (NCL).
PG  - 89-109
LID - S1876-1623(22)00066-9 [pii]
LID - 10.1016/bs.apcsb.2022.07.002 [doi]
AB  - The Neuronal Ceroid Lipofuscinoses (NCL) are a group of progressive 
      neurodegenerative disorders, associated with 14 Ceroid Lipofuscinosis Neuronal 
      genes (CLN1-14). The mutations in the Palmitoyl-Protein Thioesterase 1 (PPT1) 
      protein serve as one of the major reasons for the causative of NCL. The PPT1 
      involves degrading and modifying cysteine residues in proteins or peptides by 
      removing thioester-linked fatty acyl groups like palmitate prefers acyl chains of 
      14-18 carbons in length. In this study, we have analyzed the impact of PPT1 
      mutations on the deleteriousness, stability, conservative nature of amino acid, 
      and impact of mutations on the protein structure. We have also used molecular 
      dynamics simulations using GROMACS to perceive the alteration in the dynamic 
      behavior of the PPT1 at the residual level. In this study, we have retrieved 23 
      PPT1 mutations from the UniProt database, and these were subjected to a series of 
      analyses using varied computer algorithms. From these analyses, out of 23 
      mutations, 16 mutations were identified as deleterious. Among 16, eight mutations 
      were identified to destabilize the protein structure, and finally, two mutations 
      (W38C and L222P) were found to be positioned in the highly conserved region. The 
      structural impact study observed that the mutant proline could disrupt the alpha 
      helix formed by the leucine at position 222. Finally, from the molecular dynamics 
      simulations, we observed that due to the mutations (W38C and L222P), the protein 
      had experienced higher deviation, fluctuation, and lower compactness. These 
      structural changes elucidate that these mutations can impact the structure and 
      function of the PPT1 protein.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Thirumal Kumar, D
AU  - Thirumal Kumar D
AD  - Faculty of Allied Health Sciences, Meenakshi Academy of Higher Education and 
      Research, Chennai, Tamil Nadu, India. Electronic address: 
      thirumalkumar.d@gmail.com.
FAU - Shaikh, Nishaat
AU  - Shaikh N
AD  - Laboratory of Integrative Genomics, Department of Integrative Biology, School of 
      Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil 
      Nadu, India.
FAU - Udhaya Kumar, S
AU  - Udhaya Kumar S
AD  - Laboratory of Integrative Genomics, Department of Integrative Biology, School of 
      Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil 
      Nadu, India.
FAU - George Priya Doss, C
AU  - George Priya Doss C
AD  - Laboratory of Integrative Genomics, Department of Integrative Biology, School of 
      Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil 
      Nadu, India. Electronic address: georgepriyadoss@vit.ac.in.
LA  - eng
PT  - Journal Article
DEP - 20220818
PL  - Netherlands
TA  - Adv Protein Chem Struct Biol
JT  - Advances in protein chemistry and structural biology
JID - 101497281
RN  - 0 (Membrane Proteins)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Humans
MH  - Membrane Proteins/genetics
MH  - Mutation
MH  - *Neuronal Ceroid-Lipofuscinoses/genetics
MH  - Thiolester Hydrolases/chemistry/genetics/*metabolism
OTO - NOTNLM
OT  - Ceroid lipofuscinosis neuronal genes
OT  - Function
OT  - Molecular dynamics
OT  - Mutations
OT  - Neuronal ceroid lipofuscinoses
OT  - PPT1
COIS- Conflict of interest The authors have declared that no conflicts of interest 
      exist.
EDAT- 2022/09/11 06:00
MHDA- 2022/09/14 06:00
CRDT- 2022/09/10 21:05
PHST- 2022/09/10 21:05 [entrez]
PHST- 2022/09/11 06:00 [pubmed]
PHST- 2022/09/14 06:00 [medline]
AID - S1876-1623(22)00066-9 [pii]
AID - 10.1016/bs.apcsb.2022.07.002 [doi]
PST - ppublish
SO  - Adv Protein Chem Struct Biol. 2022;132:89-109. doi: 10.1016/bs.apcsb.2022.07.002. 
      Epub 2022 Aug 18.