5wi4 | pdb_00005wi4
CRYSTAL STRUCTURE OF DYNLT1/TCTEX-1 IN COMPLEX WITH ARHGEF2
Structural highlights
Function[DYLT1_MOUSE] Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Binds to transport cargos and is involved in apical cargo transport such as rhodopsin-bearing vesicles in polarized epithelia (By similarity). May also be a accessory component of axonemal dynein. Plays an important role in male germ cell development and function. Candidate for involvement in male sterility.[1] Plays a role in neuronal morphogenesis; the function is independent of cytoplasmic dynein and seems to be coupled to regulation of the actin cytoskeleton by enhancing Rac1 activity. The function in neurogenesis may be regulated by association with a G-protein beta-gamma dimer. May function as a receptor-independent activator of heterotrimeric G-protein signaling; the activation appears to be independent of a nucleotide exchange. Plays a role in regulating neurogenesis; inhibits the genesis of neurons from precursor cells during cortical development presumably by antagonizing ARHGEF2. Unrelated to the role in retrograde microtubule-associated movement may play a role in the dimerization of cytoplasmic proteins/domains such as for ACVR2B. Binds to the cytoplasmic domain of ACVR2B and, in vitro, inhibits ACVR2B signaling. Involved in the regulation of mitotic spindle orientation.[2] [3] Publication Abstract from PubMedThe PAR-1-MARK pathway controls cell polarity through the phosphorylation of microtubule-associated proteins. Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. Phosphorylation of ARHGEF2 by MARK3 stimulated RHOA activation and the formation of stress fibers and focal adhesions, and was required for organized cellular architecture in three-dimensional culture. Protein phosphatase 2A (PP2A) dephosphorylated Ser151 in ARHGEF2 to restore the inhibited state. Thus, we have identified a regulatory switch controlled by MARK3 that couples microtubules to the actin cytoskeleton to establish epithelial cell polarity through ARHGEF2. MARK3-mediated phosphorylation of ARHGEF2 couples microtubules to the actin cytoskeleton to establish cell polarity.,Sandi MJ, Marshall CB, Balan M, Coyaud E, Zhou M, Monson DM, Ishiyama N, Chandrakumar AA, La Rose J, Couzens AL, Gingras AC, Raught B, Xu W, Ikura M, Morrison DK, Rottapel R Sci Signal. 2017 Oct 31;10(503). pii: eaan3286. doi: 10.1126/scisignal.aan3286. PMID:29089450[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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