UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain
Kinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia....
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003681 |
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| author | Odvogmed Bayansan Prerana Bhan Chien-Yu Chang Syed Nooruzuha Barmaver Che-Piao Shen Oliver Ingvar Wagner |
| author_facet | Odvogmed Bayansan Prerana Bhan Chien-Yu Chang Syed Nooruzuha Barmaver Che-Piao Shen Oliver Ingvar Wagner |
| author_sort | Odvogmed Bayansan |
| collection | DOAJ |
| description | Kinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia. UNC-104 binds to lipid bilayers of synaptic vesicles via its C-terminal PH (pleckstrin homology) domain. Since this interaction is relatively weak and non-specific, we hypothesize that other, more specific, interaction schemes exist. From the literature, it is evident that UNC-104 regulator SYD-2 interacts with UNC-10 and that UNC-10 itself interacts with RAB-3 bound to synaptic vesicles. RT-PCR and Western blot experiments expose genetic relationships between unc-10 and syd-2, but not between unc-10 and rab-3. Also, neither unc-10 nor rab-3 affects UNC-104 expression. However, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays reveal functional interactions between UNC-104, SYD-2, UNC-10 and RAB-3. Though both SNB-1 and RAB-3 are actively transported by UNC-104, motility of RAB-3 is facilitated in the presence of SYD-2 and UNC-10. Deletion of UNC-104's PH domain did not affect UNC-104/RAB-3 colocalization, but significantly affected UNC-104/SNB-1 colocalization. Similarly, motility of RAB-3-labeled vesicles is only slightly altered in nematodes carrying a point mutation in the PH domain, whereas movement of SNB-1 is significantly reduced in this mutant. Western blots from purified fractions of synaptic vesicles reveal strong reduction of UNC-104 in rab-3/unc-10 double mutants. Our findings suggest that the UNC-10/SYD-2 complex acts as a functional linker to connect UNC-104 to RAB-3-containing vesicles. Thus, this linker complex contributes to the specificity of motor/cargo interactions. |
| format | Article |
| id | doaj-art-372471d97c0b4435bc45d6f5f8be44c7 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-372471d97c0b4435bc45d6f5f8be44c72025-01-07T04:17:09ZengElsevierNeurobiology of Disease1095-953X2025-01-01204106766UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domainOdvogmed Bayansan0Prerana Bhan1Chien-Yu Chang2Syed Nooruzuha Barmaver3Che-Piao Shen4Oliver Ingvar Wagner5National Tsing Hua University, Institute of Molecular and Cellular Biology, Department of Life Science, Hsinchu 30013, Taiwan, ROCNational Tsing Hua University, Institute of Molecular and Cellular Biology, Department of Life Science, Hsinchu 30013, Taiwan, ROCNational Tsing Hua University, Institute of Molecular and Cellular Biology, Department of Life Science, Hsinchu 30013, Taiwan, ROCNational Tsing Hua University, Institute of Molecular and Cellular Biology, Department of Life Science, Hsinchu 30013, Taiwan, ROCNational Tsing Hua University, Institute of Molecular and Cellular Biology, Department of Life Science, Hsinchu 30013, Taiwan, ROCCorresponding author at: National Tsing Hua University, Institute of Molecular and Cellular Biology & Department of Life Science, 101, Sec. 2, Kuang-Fu Road, Hsinchu 30013, Taiwan, ROC.; National Tsing Hua University, Institute of Molecular and Cellular Biology, Department of Life Science, Hsinchu 30013, Taiwan, ROCKinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia. UNC-104 binds to lipid bilayers of synaptic vesicles via its C-terminal PH (pleckstrin homology) domain. Since this interaction is relatively weak and non-specific, we hypothesize that other, more specific, interaction schemes exist. From the literature, it is evident that UNC-104 regulator SYD-2 interacts with UNC-10 and that UNC-10 itself interacts with RAB-3 bound to synaptic vesicles. RT-PCR and Western blot experiments expose genetic relationships between unc-10 and syd-2, but not between unc-10 and rab-3. Also, neither unc-10 nor rab-3 affects UNC-104 expression. However, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays reveal functional interactions between UNC-104, SYD-2, UNC-10 and RAB-3. Though both SNB-1 and RAB-3 are actively transported by UNC-104, motility of RAB-3 is facilitated in the presence of SYD-2 and UNC-10. Deletion of UNC-104's PH domain did not affect UNC-104/RAB-3 colocalization, but significantly affected UNC-104/SNB-1 colocalization. Similarly, motility of RAB-3-labeled vesicles is only slightly altered in nematodes carrying a point mutation in the PH domain, whereas movement of SNB-1 is significantly reduced in this mutant. Western blots from purified fractions of synaptic vesicles reveal strong reduction of UNC-104 in rab-3/unc-10 double mutants. Our findings suggest that the UNC-10/SYD-2 complex acts as a functional linker to connect UNC-104 to RAB-3-containing vesicles. Thus, this linker complex contributes to the specificity of motor/cargo interactions.http://www.sciencedirect.com/science/article/pii/S0969996124003681Liprin-αRIMS1RAB3AVAMP2KIF1AC. elegans |
| spellingShingle | Odvogmed Bayansan Prerana Bhan Chien-Yu Chang Syed Nooruzuha Barmaver Che-Piao Shen Oliver Ingvar Wagner UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain Neurobiology of Disease Liprin-α RIMS1 RAB3A VAMP2 KIF1A C. elegans |
| title | UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain |
| title_full | UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain |
| title_fullStr | UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain |
| title_full_unstemmed | UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain |
| title_short | UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain |
| title_sort | unc 10 syd 2 links kinesin 3 to rab 3 containing vesicles in the absence of the motor s ph domain |
| topic | Liprin-α RIMS1 RAB3A VAMP2 KIF1A C. elegans |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003681 |
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