Molecular and structural perspectives on protein trafficking to the primary cilium membrane

The primary cilium is a dynamic subcellular compartment templated from the mother centriole or basal body. Cilia are solitary and tiny, but remarkably consequential in cellular pathways regulating proliferation, differentiation, and maintenance. Multiple transmembrane proteins such as G-protein-coupled receptors, channels, enzymes, and membrane-associated lipidated proteins are enriched in the ciliary membrane. The precise regulation of ciliary membrane content is essential for effective signal transduction and maintenance of tissue homeostasis. Surprisingly, a few conserved molecular factors, intraflagellar transport complex A and the tubby family adapter protein TULP3, mediate the transport of most membrane cargoes into cilia. Recent advances in cryogenic electron microscopy provide fundamental insights into these molecular players. Here, we review the molecular players mediating cargo delivery into the ciliary membrane through the lens of structural biology. These mechanistic insights into ciliary transport provide a framework for understanding of disease variants in ciliopathies, enable precise manipulation of cilia-mediated pathways, and provide a platform for the development of targeted therapeutics.