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4mdr

From Proteopedia

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Current revision

Crystal structure of adaptor protein complex 4 (AP-4) mu4 subunit C-terminal domain D190A mutant, in complex with a sorting peptide from the amyloid precursor protein (APP)

Structural highlights

4mdr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AP4M1_HUMAN Defects in AP4M1 are the cause of cerebral palsy spastic quadriplegic type 3 (CPSQ3) [MIM:612936. A non-progressive disorder of movement and/or posture resulting from defects in the developing central nervous system. Affected individuals present postnatally with early infantile hypotonia, delayed psychomotor development, strabismus, lack of independent walking and severe mental retardation. They develop progressive spasticity of all limbs with generalized hypertonia, hyperreflexia, and extensor plantar responses by the end of the first year of life. Speech is absent or limited. Pseudobulbar signs, such as drooling, stereotypic laughter, and exaggerated jaw jerk, are part of the clinical picture.

Function

AP4M1_HUMAN Subunit of novel type of clathrin- or non-clathrin-associated protein coat involved in targeting proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system.

Publication Abstract from PubMed

Adaptor protein (AP) complexes facilitate protein trafficking by playing key roles in the selection of cargo molecules to be sorted in post-Golgi compartments. Four AP complexes (AP-1 to AP-4) contain a medium-sized subunit (mu1-mu4) that recognizes YXXO-sequences (O is a bulky hydrophobic residue), which are sorting signals in transmembrane proteins. A conserved, canonical region in mu subunits mediates recognition of YXXO-signals by means of a critical aspartic acid. Recently we found that a non-canonical YXXO-signal on the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) binds to a distinct region of the mu4 subunit of the AP-4 complex. In this study we aimed to determine the functionality of both binding sites of mu4 on the recognition of the non-canonical YXXO-signal of APP. We found that substitutions in either binding site abrogated the interaction with the APP-tail in yeast-two hybrid experiments. Further characterization by isothermal titration calorimetry showed instead loss of binding to the APP signal with only the substitution R283D at the non-canonical site, in contrast to a decrease in binding affinity with the substitution D190A at the canonical site. We solved the crystal structure of the C-terminal domain of the D190A mutant bound to this non-canonical YXXO-signal. This structure showed no significant difference compared to that of wild-type mu4. Both differential scanning fluorimetry and limited proteolysis analyses demonstrated that the D190A substitution rendered mu4 less stable, suggesting an explanation for its lower binding affinity to the APP signal. Finally, in contrast to overexpression of the D190A mutant, and acting in a dominant-negative manner, overexpression of mu4 with either a F255A or a R283D substitution at the non-canonical site halted APP transport at the Golgi apparatus. Together, our analyses support that the functional recognition of the non-canonical YXXO-signal of APP is limited to the non-canonical site of mu4.

Structural and Functional Characterization of Cargo-Binding Sites on the mu4-Subunit of Adaptor Protein Complex 4.,Ross BH, Lin Y, Corales EA, Burgos PV, Mardones GA PLoS One. 2014 Feb 3;9(2):e88147. doi: 10.1371/journal.pone.0088147. eCollection , 2014. PMID:24498434^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ross BH, Lin Y, Corales EA, Burgos PV, Mardones GA. Structural and Functional Characterization of Cargo-Binding Sites on the mu4-Subunit of Adaptor Protein Complex 4. PLoS One. 2014 Feb 3;9(2):e88147. doi: 10.1371/journal.pone.0088147. eCollection , 2014. PMID:24498434 doi:http://dx.doi.org/10.1371/journal.pone.0088147

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4mdr"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4mdr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MDR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MDR FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mdr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mdr OCA], [https://pdbe.org/4mdr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mdr RCSB], [https://www.ebi.ac.uk/pdbsum/4mdr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mdr ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mdr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mdr OCA], [https://pdbe.org/4mdr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mdr RCSB], [https://www.ebi.ac.uk/pdbsum/4mdr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mdr ProSAT]</span></td></tr>
 </table>
 == Disease ==

4mdr

From Proteopedia

Current revision

Crystal structure of adaptor protein complex 4 (AP-4) mu4 subunit C-terminal domain D190A mutant, in complex with a sorting peptide from the amyloid precursor protein (APP)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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