RT Book, Section
A1 Bross, Peter
A1 Gersting, Søren W.
A1 McCaffrey, Kitty
A1 Gremme, Sabine
A1 Muntau, Ania C.
A1 Braakman, Ineke
A1 Gregersen, Niels
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181402742
T1 Protein Folding and Misfolding: The Role of Cellular Protein Quality Control Systems in Inherited Disorders
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181402742
RD 2024/04/16
AB More  than  half  of  all  disease-causing  sequence  variations  associated  with  inherited  disorders  as  well  as  a  significant  fraction  of  single  nucleotide  polymorphisms  (SNPs)  that  may  confer  susceptibility  to  disease  conditions  are  missense  variants.Missense  variants  may  result  in  misfolding  of  the  corresponding  variant  proteins,  and  a  protein  conformational  disease  may  develop.  Dependent  on  the  protein  as  well  as  the  type  and  location  of  the  variation  in  the  particular  protein,  the  resulting  disease  can  be  categorized  as  mainly  a  loss-of-function  or  a  gain-of-function  conformational  disease.An  important  determinant  for  the  type  of  conformational  disease  is  the  ability  of  the  protein  quality  control  (PQC)  systems  of  the  cell  to  eliminate  the  misfolded  proteins  in  question.  Disorders  involving  proteins  that  are  rapidly  eliminated  develop  mainly  loss-of-function  pathologies.  Diseases  in  which  the  misfolded  protein  escapes  the  PQC  systems  and  forms  aggregates  or  toxic  dominant  negative  protein  species  often  develop  gain-of-function  pathologies  as  the  main  determinant.  All  misfolded  proteins  constitute  a  burden  on  the  cell  and  may  evoke  stress  responses.The  effect  of  a  given  missense  variation  may—as  a  first  approach—be  predicted  from  the  degree  of  evolutionary  conservation  and  physicochemical  alterations  evaluated  from  the  native  structure  of  the  protein.  However,  since  disease-causing  missense  variations  in  a  majority  of  cases  affect  folding  to  the  native  state,  and  because  for  most  proteins  folding  of  variant  proteins  cannot  yet  be  appropriately  modeled,  a  trustworthy  prediction  based  solely  on  the  position  and  type  of  replacement  is  problematic.The  acquisition  of  the  functional  structure  through  the  folding  pathway  of  wild-type  as  well  as  missense  variant  proteins  is  assisted  by  chaperones  and  supervised  by  organelle-specific  PQC  systems,  which  consist  of  chaperones,  particular  proteases,  and  regulatory  factors.The  most  important  chaperones  are  members  of  the  Hsp70  family,  the  Hsp90s,  the  small  HSPs,  and  the  chaperonins.  The  endoplasmic  reticulum  also  contains  a  number  of  lectin  chaperones  that  bind  glycosylated  proteins  and  assist  their  folding.  In  addition  to  these  general  chaperones  a  large  number  of  specialized  chaperones  exist  that  assist  in  the  folding  and  assembly  of  specific  protein  complexes,  such  as  respiratory  chain  complexes.  The  proteases  of  the  PQC  systems  constitute  a  large  variety  of  organelle-specific  complexes,  of  which  the  proteasome  and  the  AAA+-domain  proteases  are  the  most  important.The  PQC  systems  are  involved  in  the  biogenesis  of  newly  synthesized  proteins  by  supervising  the  acquisition  of  the  functional  structure.  A  large  number  of  newly  synthesized  protein  molecules—up  to  30%—never  reach  the  native  structure,  because  either  they  carry  transcriptional/translational  errors  or  they  carry  missense  sequence  variations.  Efficient  PQC  systems  are  thus  necessary  for  the  proper  function  of  the  cell.  If  the  systems  are  not  efficient,  either  because  of  the  extra  load  added  by  genetic  defects  or  as  a  consequence  of  age-dependent  decline,  misfolded  proteins  accumulate  and  may  give  rise  to  aggregation/gain-of-function  diseases.  On  the  other  hand,  in  loss-of-function  disorders  where  the  misfolded  variant  protein  is  eliminated,  the  efficiency  of  the  PQC  systems  will  be  determining  for  the  degree  of  functional  deficiency  and  thereby  for  the  clinical  expression.In  addition  to  the  protein  in  question,  the  type  and  location  of  the  sequence  variation,  and  the  ...