A Structural Model for the Core Nup358-BicD2 Interface

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2023 Oct 28

PMID 37892127

Authors

James M Gibson

Xiaoxin Zhao

M Yusuf Ali

Sozanne R Solmaz

Chunyu Wang

Affiliations

Soon will be listed here.

Abstract

Dynein motors facilitate the majority of minus-end-directed transport events on microtubules. The dynein adaptor Bicaudal D2 (BicD2) recruits the dynein machinery to several cellular cargo for transport, including Nup358, which facilitates a nuclear positioning pathway that is essential for the differentiation of distinct brain progenitor cells. Previously, we showed that Nup358 forms a "cargo recognition α-helix" upon binding to BicD2; however, the specifics of the BicD2-Nup358 interface are still not well understood. Here, we used AlphaFold2, complemented by two additional docking programs (HADDOCK and ClusPro) as well as mutagenesis, to show that the Nup358 cargo-recognition α-helix binds to BicD2 between residues 747 and 774 in an anti-parallel manner, forming a helical bundle. We identified two intermolecular salt bridges that are important to stabilize the interface. In addition, we uncovered a secondary interface mediated by an intrinsically disordered region of Nup358 that is directly N-terminal to the cargo-recognition α-helix and binds to BicD2 between residues 774 and 800. This is the same BicD2 domain that binds to the competing cargo adapter Rab6, which is important for the transport of Golgi-derived and secretory vesicles. Our results establish a structural basis for cargo recognition and selection by the dynein adapter BicD2, which facilitates transport pathways that are important for brain development.

Citing Articles

ZYG-12/Hook's dual role as a dynein adaptor for early endosomes and nuclei is regulated by alternative splicing of its cargo binding domain.

Carvalho C, Moreira M, Barbosa D, Chan F, Koehnen C, Teixeira V Mol Biol Cell. 2024; 36(2):ar19.

PMID: 39718769 PMC: 11809306. DOI: 10.1091/mbc.E24-08-0364.

Advances in the understanding of nuclear pore complexes in human diseases.

Li Y, Zhu J, Zhai F, Kong L, Li H, Jin X J Cancer Res Clin Oncol. 2024; 150(7):374.

PMID: 39080077 PMC: 11289042. DOI: 10.1007/s00432-024-05881-5.

Molecular mechanism for recognition of the cargo adapter Rab6 by the dynein adapter BicD2.

Zhao X, Quintremil S, Rodriguez Castro E, Cui H, Moraga D, Wang T Life Sci Alliance. 2024; 7(7).

PMID: 38719748 PMC: 11077774. DOI: 10.26508/lsa.202302430.

References

Vajda S, Yueh C, Beglov D, Bohnuud T, Mottarella S, Xia B . New additions to the ClusPro server motivated by CAPRI. Proteins. 2016; 85(3):435-444. PMC: 5313348. DOI: 10.1002/prot.25219. View

Mosalaganti S, Obarska-Kosinska A, Siggel M, Taniguchi R, Turonova B, Zimmerli C . AI-based structure prediction empowers integrative structural analysis of human nuclear pores. Science. 2022; 376(6598):eabm9506. DOI: 10.1126/science.abm9506. View

Rossor A, Sleigh J, Groves M, Muntoni F, Reilly M, Hoogenraad C . Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy. Acta Neuropathol Commun. 2020; 8(1):34. PMC: 7076953. DOI: 10.1186/s40478-020-00909-6. View

McKenney R, Huynh W, Tanenbaum M, Bhabha G, Vale R . Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes. Science. 2014; 345(6194):337-41. PMC: 4224444. DOI: 10.1126/science.1254198. View

Gallisa-Sune N, Sanchez-Fernandez-de-Landa P, Zimmermann F, Serna M, Regue L, Paz J . BICD2 phosphorylation regulates dynein function and centrosome separation in G2 and M. Nat Commun. 2023; 14(1):2434. PMC: 10140047. DOI: 10.1038/s41467-023-38116-1. View

van Zundert G, Rodrigues J, Trellet M, Schmitz C, Kastritis P, Karaca E . The HADDOCK2.2 Web Server: User-Friendly Integrative Modeling of Biomolecular Complexes. J Mol Biol. 2015; 428(4):720-725. DOI: 10.1016/j.jmb.2015.09.014. View

Pernigo S, Lamprecht A, Steiner R, Dodding M . Structural basis for kinesin-1:cargo recognition. Science. 2013; 340(6130):356-9. PMC: 3693442. DOI: 10.1126/science.1234264. View

Hu D, Baffet A, Nayak T, Akhmanova A, Doye V, Vallee R . Dynein recruitment to nuclear pores activates apical nuclear migration and mitotic entry in brain progenitor cells. Cell. 2013; 154(6):1300-13. PMC: 3822917. DOI: 10.1016/j.cell.2013.08.024. View

Cui H, Ali M, Goyal P, Zhang K, Loh J, Trybus K . Coiled-coil registry shifts in the F684I mutant of Bicaudal D result in cargo-independent activation of dynein motility. Traffic. 2020; 21(7):463-478. PMC: 7437983. DOI: 10.1111/tra.12734. View

10.

Encalada S, Szpankowski L, Xia C, Goldstein L . Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles. Cell. 2011; 144(4):551-65. PMC: 3576050. DOI: 10.1016/j.cell.2011.01.021. View

11.

Sladewski T, Billington N, Ali M, Bookwalter C, Lu H, Krementsova E . Recruitment of two dyneins to an mRNA-dependent Bicaudal D transport complex. Elife. 2018; 7. PMC: 6056235. DOI: 10.7554/eLife.36306. View

12.

Fagiewicz R, Crucifix C, Klos T, Deville C, Kieffer B, Nomine Y . In vitro characterization of the full-length human dynein-1 cargo adaptor BicD2. Structure. 2022; 30(11):1470-1478.e3. DOI: 10.1016/j.str.2022.08.009. View

13.

Peeters K, Litvinenko I, Asselbergh B, Almeida-Souza L, Chamova T, Geuens T . Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. Am J Hum Genet. 2013; 92(6):955-64. PMC: 3675262. DOI: 10.1016/j.ajhg.2013.04.013. View

14.

Soppina V, Rai A, Ramaiya A, Barak P, Mallik R . Tug-of-war between dissimilar teams of microtubule motors regulates transport and fission of endosomes. Proc Natl Acad Sci U S A. 2009; 106(46):19381-6. PMC: 2770008. DOI: 10.1073/pnas.0906524106. View

15.

Chaaban S, Carter A . Structure of dynein-dynactin on microtubules shows tandem adaptor binding. Nature. 2022; 610(7930):212-216. PMC: 7613678. DOI: 10.1038/s41586-022-05186-y. View

16.

Hendricks A, Perlson E, Ross J, Schroeder 3rd H, Tokito M, Holzbaur E . Motor coordination via a tug-of-war mechanism drives bidirectional vesicle transport. Curr Biol. 2010; 20(8):697-702. PMC: 2908734. DOI: 10.1016/j.cub.2010.02.058. View

17.

Fu M, Holzbaur E . Integrated regulation of motor-driven organelle transport by scaffolding proteins. Trends Cell Biol. 2014; 24(10):564-74. PMC: 4177981. DOI: 10.1016/j.tcb.2014.05.002. View

18.

Cui H, Noell C, Behler R, Zahn J, Terry L, Russ B . Adapter Proteins for Opposing Motors Interact Simultaneously with Nuclear Pore Protein Nup358. Biochemistry. 2019; 58(50):5085-5097. PMC: 7243271. DOI: 10.1021/acs.biochem.9b00907. View

19.

Urnavicius L, Zhang K, Diamant A, Motz C, Schlager M, Yu M . The structure of the dynactin complex and its interaction with dynein. Science. 2015; 347(6229):1441-1446. PMC: 4413427. DOI: 10.1126/science.aaa4080. View

20.

Kozakov D, Beglov D, Bohnuud T, Mottarella S, Xia B, Hall D . How good is automated protein docking?. Proteins. 2013; 81(12):2159-66. PMC: 3934018. DOI: 10.1002/prot.24403. View