TY  - JOUR
A1  - Lüningschrör, Patrick
A1  - Binotti, Beyenech
A1  - Dombert, Benjamin
A1  - Heimann, Peter
A1  - Perez-Lara, Angel
A1  - Slotta, Carsten
A1  - Thau-Habermann, Nadine
A1  - von Collenberg, Cora R.
A1  - Karl, Franziska
A1  - Damme, Markus
A1  - Horowitz, Arie
A1  - Maystadt, Isabelle
A1  - Füchtbauer, Annette
A1  - Füchtbauer, Ernst-Martin
A1  - Jablonka, Sibylle
A1  - Blum, Robert
A1  - Üçeyler, Nurcan
A1  - Petri, Susanne
A1  - Kaltschmidt, Barbara
A1  - Jahn, Reinhard
A1  - Kaltschmidt, Christian
A1  - Sendtner, Michael
T1  - Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
JF  - Nature Communications
N2  - Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
KW  - autophagy
KW  - synaptic vesicles
KW  - Pleckstrin homology containing family member 5 (Plekhg5)
KW  - regulation
KW  - motoneuron disease
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170048
VL  - 8
IS  - 678
ER  - 
TY  - JOUR
A1  - Metje-Sprink, Janina
A1  - Groffmann, Johannes
A1  - Neumann, Piotr
A1  - Barg-Kues, Brigitte
A1  - Ficner, Ralf
A1  - Kühnel, Karin
A1  - Schalk, Amanda M.
A1  - Binotti, Beyenech
T1  - Crystal structure of the Rab33B/Atg16L1 effector complex
JF  - Scientific Reports
N2  - The Atg12-Atg5/Atg16L1 complex is recruited by WIPI2b to the site of autophagosome formation. Atg16L1 is an effector of the Golgi resident GTPase Rab33B. Here we identified a minimal stable complex of murine Rab33B(30-202) Q92L and Atg16L1(153-210). Atg16L1(153-210) comprises the C-terminal part of the Atg16L1 coiled-coil domain. We have determined the crystal structure of the Rab33B Q92L/Atg16L1(153-210) effector complex at 3.47 angstrom resolution. This structure reveals that two Rab33B molecules bind to the diverging alpha -helices of the dimeric Atg16L1 coiled-coil domain. We mutated Atg16L1 and Rab33B interface residues and found that they disrupt complex formation in pull-down assays and cellular co-localization studies. The Rab33B binding site of Atg16L1 comprises 20 residues and immediately precedes the WIPI2b binding site. Rab33B mutations that abolish Atg16L binding also abrogate Rab33B association with the Golgi stacks. Atg16L1 mutants that are defective in Rab33B binding still co-localize with WIPI2b in vivo. The close proximity of the Rab33B and WIPI2b binding sites might facilitate the recruitment of Rab33B containing vesicles to provide a source of lipids during autophagosome biogenesis.
KW  - autophagosome formation
KW  - ATG12-ATG5 conjugate
KW  - LC3 lipidation
KW  - binding sites
KW  - ATG proteins
KW  - RAB GTPases
KW  - family
KW  - membrane
KW  - recognition
KW  - proppins
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230396
VL  - 10
ER  -