The cytoplasmic dynein transport machinery and its many cargoes

Abstract

Cytoplasmic dynein 1 is an important microtubule-based motor in many eukaryotic cells. Dynein has critical roles both in interphase and during cell division. Here, we focus on interphase cargoes of dynein, which include membrane-bound organelles, RNAs, protein complexes and viruses. A central challenge in the field is to understand how a single motor can transport such a diverse array of cargoes and how this process is regulated. The molecular basis by which each cargo is linked to dynein and its cofactor dynactin has started to emerge. Of particular importance for this process is a set of coiled-coil proteins - activating adaptors - that both recruit dynein-dynactin to their cargoes and activate dynein motility.

Figure 1 |. The dynein transport machinery.

a | Cartoon of cytoplasmic dynein-1. The two dynein heavy chains (DHCs) are linked together by an amino-terminal dimerization domain (NDD) and have a carboxy-terminal motor domain with a microtubule binding domain (MTDB) at the end of a long anti parallel coiled-coil stalk. The intermediate chains (DIC) have extended amino-termini that bind dimers of the light chains Roadblock (Robl), LC8 and Tctex. The light intermediate chain (DLIC) has an extended carboxy-terminus. b | Structure of the dynein tail^, (PDBs 6F1T and 5NVU) showing the amino-terminal dimerization domain (NDD) and nine helical bundles (1–9; neighbouring bundles are shown in different shades of blue to distinguish them) in the DHC and depicting interactions of DHC with DIC and DLIC. The DIC WD40 domain binds bundles 4 and 5, whereas the Ras-like domain of DLIC binds to bundles 5 and 7, using its amino- and carboxy-terminal helices (α1 and α13). The DIC and DLIC extended termini are not shown. The structure of helical bundles 8 and 9 is approximate. c | Dynactin is built around a filament of eight actin related proteins (Arp1). At the barbed end are capping proteins (CapZ). At the pointed end is an actin monomer, another actin related protein (Arp11) and a complex of three proteins (p62, p27 and p25). The shoulder domain binds the filament via extended amino-terminal peptides of p50/dynamitin. The p150 component extends from the shoulder, containing stretches of coiled-coil (CC2, CC1b and CC1a). At the amino-terminus of p150 are the basic and CAP-Gly domains that can interact with microtubules. d | Domain structure of known and candidate activating adaptors (see also Table 1). Reported sites of interactions are indicated above each cartoon. Key shows domains identified in the literature or by InterPro. RH1 and RH2, RILP homology 1 and 2. e | Dynein–dynactin–activator complexes on microtubules. The activating adaptors BICD2 or BICDL1 run along the dynactin filament and recruit the dynein heavy chains. BICD2 preferentially recruits one dynein dimer (left), whereas BICDL1 recruits two dimers (right).

Figure 2 |. Many cargoes of dynein and their activating adaptors.

Many of the dynein cargoes discussed in this Review. Some cargoes are trafficked along microtubules, while in other cases the role of dynein is to position them. Known activating adaptors are marked with a star. Candidate activating adaptors are also listed.

Figure 3 |. Mechanisms linking dynein and dynactin to membrane cargoes.

a | Dynein– dynactin associates with Golgi-derived vesicles using the activating adaptors BICD2 or BICDL1 depending on the cell type. Both BICD2 and BICDL1 bind, via their carboxy-terminal coiled-coils, to a dimer of the small GTPase Rab6. Rab6 binds to Golgi-derived membranes via its prenyl tails, as do other Rabs. b | Early endosomes recruit dynein–dynactin via the activating adaptors HOOK1 or HOOK3. These adaptors bind the FTS and FHIP proteins to form the FHF complex. FHIP is reported to bind directly to the early endosome marker Rab5. Rab5 also binds Htt, which is linked to HAP1, another potential activating adaptor. The PI3P binding protein ANK-B binds the pointed end of dynactin and is also important for early endosome transport. How these and other dynein–dynactin adaptors work together is unknown. c | Late endosomes are marked with Rab7, which binds RILP and the cholesterol sensor ORP1L. RILP binds the DLIC. RILP also binds the HOPS complex, which interacts with the FHF complex, raising the possibility that HOOK proteins also link dynein–dynactin to late endosomes. As with early endosomes, other potential dynein–dynactin links have been reported for the movement of late endosomes. d | In filamentous fungi some cargos (peroxisomes, ER, lipid droplets, and RNPs) associate with the dynein transport machinery indirectly by hitchhiking on early endosomes, which can directly recruit the transport machinery via the Hook-containing FHF complex (see part b). PxdA is a putative tether that links peroxisomes to early endosomes although how it interacts with both peroxisomes and early endosomes is unknown.