PMID- 25342746
OWN - NLM
STAT- MEDLINE
DCOM- 20150421
LR  - 20220408
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 51
DP  - 2014 Dec 19
TI  - Structure of transmembrane domain of lysosome-associated membrane protein type 2a 
      (LAMP-2A) reveals key features for substrate specificity in chaperone-mediated 
      autophagy.
PG  - 35111-23
LID - 10.1074/jbc.M114.609446 [doi]
AB  - Chaperone-mediated autophagy (CMA) is a highly regulated cellular process that 
      mediates the degradation of a selective subset of cytosolic proteins in 
      lysosomes. Increasing CMA activity is one way for a cell to respond to stress, 
      and it leads to enhanced turnover of non-critical cytosolic proteins into sources 
      of energy or clearance of unwanted or damaged proteins from the cytosol. The 
      lysosome-associated membrane protein type 2a (LAMP-2A) together with a complex of 
      chaperones and co-chaperones are key regulators of CMA. LAMP-2A is a 
      transmembrane protein component for protein translocation to the lysosome. Here 
      we present a study of the structure and dynamics of the transmembrane domain of 
      human LAMP-2A in n-dodecylphosphocholine micelles by nuclear magnetic resonance 
      (NMR). We showed that LAMP-2A exists as a homotrimer in which the 
      membrane-spanning helices wrap around each other to form a parallel coiled coil 
      conformation, whereas its cytosolic tail is flexible and exposed to the cytosol. 
      This cytosolic tail of LAMP-2A interacts with chaperone Hsc70 and a CMA substrate 
      RNase A with comparable affinity but not with Hsp40 and RNase S peptide. Because 
      the substrates and the chaperone complex can bind at the same time, thus creating 
      a bimodal interaction, we propose that substrate recognition by chaperones and 
      targeting to the lysosomal membrane by LAMP-2A are coupled. This can increase 
      substrate affinity and specificity as well as prevent substrate aggregation, 
      assist in the unfolding of the substrate, and promote the formation of the higher 
      order complex of LAMP-2A required for translocation.
CI  - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Rout, Ashok K
AU  - Rout AK
AD  - From the Laboratory of Molecular Biophysics and.
FAU - Strub, Marie-Paule
AU  - Strub MP
AD  - From the Laboratory of Molecular Biophysics and.
FAU - Piszczek, Grzegorz
AU  - Piszczek G
AD  - Biophysics Core, Biochemistry and Biophysics Center, NHLBI, National Institutes 
      of Health, Bethesda, Maryland 20892.
FAU - Tjandra, Nico
AU  - Tjandra N
AD  - From the Laboratory of Molecular Biophysics and tjandran@nhlbi.nih.gov.
LA  - eng
SI  - PDB/2MOF
SI  - PDB/2MOM
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20141022
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (HSC70 Heat-Shock Proteins)
RN  - 0 (LAMP2 protein, human)
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - 0 (Micelles)
RN  - 0 (Molecular Chaperones)
RN  - 107-73-3 (Phosphorylcholine)
RN  - 53949-18-1 (dodecylphosphocholine)
SB  - IM
MH  - Amino Acid Sequence
MH  - *Autophagy
MH  - HSC70 Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Kinetics
MH  - Lysosomal-Associated Membrane Protein 2/*chemistry/genetics/*metabolism
MH  - Magnetic Resonance Spectroscopy/methods
MH  - Micelles
MH  - Models, Molecular
MH  - Molecular Chaperones/*metabolism
MH  - Molecular Sequence Data
MH  - Phosphorylcholine/analogs & derivatives/chemistry
MH  - Protein Binding
MH  - Protein Multimerization
MH  - Protein Structure, Secondary
MH  - *Protein Structure, Tertiary
MH  - Substrate Specificity
PMC - PMC4271201
OTO - NOTNLM
OT  - Autophagy
OT  - CMA
OT  - Chaperone
OT  - DPC
OT  - LAMP-2
OT  - Micelles
OT  - Nuclear Magnetic Resonance (NMR)
OT  - Protein Structure
OT  - Transport
EDAT- 2014/10/25 06:00
MHDA- 2015/04/22 06:00
PMCR- 2015/12/19
CRDT- 2014/10/25 06:00
PHST- 2014/10/25 06:00 [entrez]
PHST- 2014/10/25 06:00 [pubmed]
PHST- 2015/04/22 06:00 [medline]
PHST- 2015/12/19 00:00 [pmc-release]
AID - S0021-9258(19)56050-1 [pii]
AID - M114.609446 [pii]
AID - 10.1074/jbc.M114.609446 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Dec 19;289(51):35111-23. doi: 10.1074/jbc.M114.609446. Epub 
      2014 Oct 22.