CLTC

CLTC Full Name

clathrin, heavy polypeptide (Hc)

CLTC Introduction

CLTC, officially designated as clathrin, heavy polypeptide (Hc), is a protein-coding gene located on human chromosome 17q23.1. It encodes the heavy chain subunit of clathrin, a triskelion-shaped protein that forms the outer coat of coated vesicles. Unlike its paralog, CHC22 (encoded by CLTCL1), CLTC is ubiquitously expressed in nearly all mammalian tissues and is considered the classical clathrin heavy chain. Its primary function is to provide structural rigidity and mechanical force for membrane budding events, making it an indispensable component of intracellular trafficking networks.Each CLTC monomer is a large polypeptide of approximately 1,675 amino acids, with a calculated molecular weight of ~192 kDa. The protein adopts a leg-and-ankle conformation, where the N-terminal β-propeller domain binds adaptor proteins and accessory factors, while the C-terminal α-zigzag region mediates trimerization into the characteristic three-legged triskelion. Three heavy chains intertwine at their carboxyl termini, forming a vertex, while each leg extends outward as a flexible arm. This geometry allows CLTC to self-assemble into curved polyhedral lattices that drive vesicle invagination—a remarkable example of how quaternary structure enables dynamic membrane remodeling.

Figure1. Structure of CLTC.(Matteo F, Diekmann Y, Camus S M, et al. 2018)

Dynamic Role in Endocytic Pathways
CLTC is the primary driver of clathrin-mediated endocytosis (CME), the major route for internalizing cell-surface receptors, nutrients, and signaling molecules. At the plasma membrane, CLTC cooperates with adaptor protein complexes (AP-2) and hundreds of auxiliary proteins to generate constricted pits. Beyond the plasma membrane, CLTC also participates in trafficking between the trans-Golgi network and endosomes, as well as in synaptic vesicle recycling at neuronal terminals. Recent studies highlight that CLTC is not a passive scaffold; its conformational changes, influenced by phosphorylation and ATPase activity of Hsc70, actively regulate coat disassembly—ensuring that vesicle uncoating occurs precisely after scission.

Pathophysiological Implications of CLTC Dysregulation
While complete CLTC knockout is embryonically lethal in mice, partial loss-of-function or aberrant expression has been linked to human disease. Somatic mutations in CLTC are recurrently observed in certain lymphomas and gastric cancers, though their oncogenic significance remains under investigation. More definitively, autosomal-dominant mutations in CLTC cause a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and distinctive facial features—often accompanied by brain MRI abnormalities such as thin corpus callosum. These clinical observations underscore that CLTC-mediated trafficking is critical for neuronal differentiation and synaptic maintenance, not merely a housekeeping process.

Alternate Names for CLTC

CLTC; clathrin, heavy polypeptide (Hc); CHC; R74732; 3110065L21Rik; clathrin heavy chain 1;

• 1.Matteo F, Diekmann Y, Camus S M, et al. Evolution of the CLTCL1 Gene Encoding CHC22 Clathrin Reveals Selection Influencing CHC22's Role in Human Glucose Metabolism. bioRxiv, 2018: 307264.