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PDBsum entry 3r68
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Signaling protein
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PDB id
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3r68
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PDB id:
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| Name: |
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Signaling protein
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Title:
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Molecular analysis of the pdz3 domain of pdzk1
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Structure:
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Na(+)/h(+) exchange regulatory cofactor nhe-rf3. Chain: a. Fragment: pdz3 (unp residues 237-323). Synonym: nherf-3, cftr-associated protein of 70 kda, na(+)/h(+) exchanger regulatory factor 3, na/pi cotransporter c-terminal- associated protein 1, napi-cap1, pdz domain-containing protein 1, sodium-hydrogen exchanger regulatory factor 3. Engineered: yes
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Gene: cap70, nherf3, pdzk1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.30Å
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R-factor:
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0.132
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R-free:
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0.157
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Authors:
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O.Kocher,G.Birrane,M.Krieger
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Key ref:
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O.Kocher
et al.
(2011).
Identification of the PDZ3 domain of the adaptor protein PDZK1 as a second, physiologically functional binding site for the C terminus of the high density lipoprotein receptor scavenger receptor class B type I.
J Biol Chem,
286,
25171-25186.
PubMed id:
DOI:
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Date:
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21-Mar-11
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Release date:
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18-May-11
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PROCHECK
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Headers
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References
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Q9JIL4
(NHRF3_MOUSE) -
Na(+)/H(+) exchange regulatory cofactor NHE-RF3 from Mus musculus
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Seq:
Struc:
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519 a.a.
85 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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J Biol Chem
286:25171-25186
(2011)
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PubMed id:
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Identification of the PDZ3 domain of the adaptor protein PDZK1 as a second, physiologically functional binding site for the C terminus of the high density lipoprotein receptor scavenger receptor class B type I.
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O.Kocher,
G.Birrane,
A.Yesilaltay,
S.Shechter,
R.Pal,
K.Daniels,
M.Krieger.
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ABSTRACT
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The normal expression, cell surface localization, and function of the murine
high density lipoprotein receptor scavenger receptor class B type I (SR-BI) in
hepatocytes in vivo, and thus normal lipoprotein metabolism, depend on its four
PDZ domain (PDZ1-PDZ4) containing cytoplasmic adaptor protein PDZK1. Previous
studies showed that the C terminus of SR-BI ("target peptide") binds
directly to PDZ1 and influences hepatic SR-BI protein expression. Unexpectedly
an inactivating mutation in PDZ1 (Tyr(20) → Ala) only partially, rather than
completely, suppresses the ability of PDZK1 to control hepatic SR-BI. We used
isothermal titration calorimetry to show that PDZ3, but not PDZ2 or PDZ4, can
also bind the target peptide (K(d) = 37.0 μm), albeit with ∼10-fold lower
affinity than PDZ1. This binding is abrogated by a Tyr(253) → Ala
substitution. Comparison of the 1.5-Å resolution crystal structure of PDZ3
with its bound target peptide ((505)QEAKL(509)) to that of peptide-bound PDZ1
indicated fewer target peptide stabilizing atomic interactions (hydrogen bonds
and hydrophobic interactions) in PDZ3. A double (Tyr(20) → Ala (PDZ1) +
Tyr(253) → Ala (PDZ3)) substitution abrogated all target peptide binding to
PDZK1. In vivo hepatic expression of a singly substituted (Tyr(253) → Ala
(PDZ3)) PDZK1 transgene (Tg) was able to correct all of the SR-BI-related
defects in PDZK1 knock-out mice, whereas the doubly substituted [Tyr(20) → Ala
(PDZ1) + Tyr(253) → Ala (PDZ3)]Tg was unable to correct these defects. Thus,
we conclude that PDZK1-mediated control of hepatic SR-BI requires direct binding
of the SR-BI C terminus to either the PDZ1 or PDZ3 domains, and that binding to
both domains simultaneously is not required for PDZK1 control of hepatic SR-BI.
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