Diversity of Clathrin Function: New Tricks for an Old Protein

Abstract

Clathrin is considered the prototype vesicle coat protein whose self-assembly mediates sorting of membrane cargo and recruitment of lipid modifiers. Detailed knowledge of clathrin biochemistry, structure, and interacting proteins has accumulated since the first observation, almost 50 years ago, of its role in receptor-mediated endocytosis of yolk protein. This review summarizes that knowledge, and focuses on properties of the clathrin heavy and light chain subunits and interaction of the latter with Hip proteins, to address the diversity of clathrin function beyond conventional receptor-mediated endocytosis. The distinct functions of the two human clathrin isoforms (CHC17 and CHC22) are discussed, highlighting CHC22's specialized involvement in traffic of the GLUT4 glucose transporter and consequent role in human glucose metabolism. Analysis of clathrin light chain function and interaction with the actin-binding Hip proteins during bacterial infection defines a novel actin-organizing function for CHC17 clathrin. By considering these diverse clathrin functions, along with intracellular sorting roles and influences on mitosis, further relevance of clathrin function to human health and disease is established.

Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

“…clathrin light chain | endocytosis | antibody isotype switch | TGFβ | G protein-coupled receptors C lathrin-coated vesicles (CCVs) influence cell signaling by selecting membrane cargo during endocytosis (1). Clathrin consists of three clathrin heavy chain (CHC17) subunits, each associated with a clathrin light chain (CLC), configured into a three-legged triskelion.…”

“…CLCs are also required for uptake of large particles, including some viruses and bacteria (6,7). These roles for CLCs in cargo selection and their general contribution to clathrin function have been a matter of speculation for some time, with indications from in vitro experiments that CLCs regulate clathrin assembly (8) and the tensile strength of the clathrin lattice (1,9). To assess such roles for CLCs in clathrin function in vivo, we made mutant mice that lack the CLTA gene, and we report their phenotype here.…”

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

“…Unlike in humans, only a pseudogene exists in mice (Wakeham et al, 2005;Vassilopoulos et al, 2009). In addition, CHC22 appears to be biochemically and functionally distinct with unique protein-protein interactions and transport properties (Wakeham et al, 2005;Brodsky, 2012). For example, CHC22 does not bind the classic adapter proteins or Golgilocalized, γ-ear-containing Arf-binding proteins that CHC17 interacts with, but directly binds to the membrane cargo recognition family member sorting nexin 5 abundant in skeletal muscle through a coiled-coil domain absent in CHC17 (Towler et al, 2004a,b).…”

Novel clathrin activity: developments in health and disease

“…Identical heavy chains associate to form the characteristic three-legged pinwheel (triskelion) (2). The N-terminal domain (NTD) of CHC17 heavy chain is folded into a seven-bladed β propeller (3).…”

“…Over 35 years ago, clathrin was found to self-assemble into a lattice coat over budding vesicles in receptor-mediated endocytosis (1,2). However, evidence has come to light that clathrin is a multi-talented protein involved in activities that go beyond conventional endocytosis.…”