4XC2

Crystal structure of GABARAP in complex with KBTBD6 LIR peptide

Summary for 4XC2

• Entry DOI: 10.2210/pdb4xc2/pdb
• Descriptor: GABA(A) receptor-associated protein, Kelch repeat and BTB domain-containing protein 6 (3 entities in total)
• Functional Keywords: autophagy, complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 60540.91

Authors

Huber, J.,Genau, H.M.,Baschieri, F.,Doetsch, V.,Farhan, H.,Rogov, V.V.,Behrends, C.,Akutsu, M. (deposition date: 2014-12-17, release date: 2015-03-04, Last modification date: 2024-01-10)

Primary citation

Genau, H.M.,Huber, J.,Baschieri, F.,Akutsu, M.,Dotsch, V.,Farhan, H.,Rogov, V.,Behrends, C.
CUL3-KBTBD6/KBTBD7 Ubiquitin Ligase Cooperates with GABARAP Proteins to Spatially Restrict TIAM1-RAC1 Signaling.
Mol.Cell, 57:995-1010, 2015

PubMed Abstract: The small Rho GTPase RAC1 is an essential regulator of cellular signaling that controls actin rearrangements and cell motility. Here, we identify a novel CUL3 RING ubiquitin ligase complex, containing the substrate adaptors KBTBD6 and KBTBD7, that mediates ubiquitylation and proteasomal degradation of TIAM1, a RAC1-specific GEF. Increasing the abundance of TIAM1 by depletion of KBTBD6 and/or KBTBD7 leads to elevated RAC1 activity, changes in actin morphology, loss of focal adhesions, reduced proliferation, and enhanced invasion. KBTBD6 and KBTBD7 employ ATG8 family-interacting motifs to bind preferentially to GABARAP proteins. Surprisingly, ubiquitylation and degradation of TIAM1 by CUL3(KBTBD6/KBTBD7) depends on its binding to GABARAP proteins. Our study reveals that recruitment of CUL3(KBTBD6/KBTBD7) to GABARAP-containing vesicles regulates the abundance of membrane-associated TIAM1 and subsequently spatially restricted RAC1 signaling. Besides their role in autophagy and trafficking, we uncovered a previously unknown function of GABARAP proteins as membrane-localized signaling scaffolds.

PubMed: 25684205
DOI: 10.1016/j.molcel.2014.12.040

Experimental method

X-RAY DIFFRACTION (1.9 Å)