7mzz

<StructureSection load='7mzz' size='340' side='right'caption='[[7mzz]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>

<table><tr><td colspan='2'>[[7mzz]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MZZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MZZ FirstGlance]. <br>

</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7mzx|7mzx]], [[7mzw|7mzw]], [[7mzy|7mzy]], [[7n00|7n00]]</div></td></tr>

== Function ==

[[https://www.uniprot.org/uniprot/ALKL1_HUMAN ALKL1_HUMAN]] Ligand for receptor tyrosine kinase LTK and perhaps receptor tyrosine kinase ALK; activation of ALK is reported conflictingly.<ref>PMID:25331893</ref> <ref>PMID:26418745</ref> <ref>PMID:26630010</ref>

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== Publication Abstract from PubMed ==

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system(1,2). The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies(3). Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma(4-7). ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain(8,9). ALK is activated by the binding of ALKAL1 and ALKAL2 ligands(10-14) to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.

Mechanism for the activation of the anaplastic lymphoma kinase receptor.,Reshetnyak AV, Rossi P, Myasnikov AG, Sowaileh M, Mohanty J, Nourse A, Miller DJ, Lax I, Schlessinger J, Kalodimos CG Nature. 2021 Dec;600(7887):153-157. doi: 10.1038/s41586-021-04140-8. Epub 2021, Nov 24. PMID:34819673<ref>PMID:34819673</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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<div class="pdbe-citations 7mzz" style="background-color:#fffaf0;"></div>

== References ==

<references/>

[[Category: Kalodimos, C G]]

[[Category: Reshetnyak, A V]]

[[Category: Rossi, P]]

[[Category: Sowaileh, M]]

[[Category: Fam150b]]