Receptor Mediated Endocytosis: Steps, Sorting, and Disease

Cells rely on receptor-mediated endocytosis (RME) to selectively internalize molecules such as nutrients, hormones, and signaling proteins. This process ensures that only specific substances enter the cell while maintaining tight regulation over cellular function. Dysfunction in RME can lead to diseases ranging from neurodegenerative disorders to viral infections.

Steps Involved In Receptor-Mediated Endocytosis

Receptor-mediated endocytosis begins when ligands such as low-density lipoproteins (LDL), transferrin, or growth factors bind to their corresponding receptors on the plasma membrane. These transmembrane proteins recognize and capture target molecules with high specificity. The binding event triggers a conformational change, facilitating the recruitment of adaptor proteins that link the receptor-ligand complex to the intracellular endocytic machinery. This ensures that only designated molecules are internalized.

Once receptor-ligand complexes cluster, the plasma membrane invaginates, forming a pit enriched with structural proteins. Cytoskeletal components and scaffolding proteins help shape and stabilize the developing vesicle. As the curvature deepens, regulatory proteins coordinate the recruitment of molecular machinery responsible for vesicle scission.

Membrane fission, mediated by the GTPase dynamin, is the final step. Dynamin assembles around the neck of the budding vesicle and, upon GTP hydrolysis, constricts the membrane, detaching the vesicle from the plasma membrane. The newly formed vesicle, initially coated with structural proteins, undergoes rapid uncoating to allow further processing.

Role Of Clathrin-Coated Vesicles

Clathrin-coated vesicles (CCVs) facilitate receptor-mediated endocytosis by internalizing specific cargo while maintaining cellular organization. These vesicles derive their name from clathrin, a protein that assembles into a lattice-like structure on the cytoplasmic side of the membrane. This arrangement, composed of triskelion-shaped clathrin subunits, provides structural integrity and flexibility, enabling uniform vesicle formation.

Adaptor proteins such as AP-2 selectively link cargo receptors to the clathrin scaffold, ensuring only designated molecules are enclosed. Accessory proteins fine-tune vesicle assembly, modulating size, curvature, and timing of membrane scission. Epsin introduces curvature-inducing interactions, while dynamin facilitates vesicle detachment by constricting the neck of the budding vesicle. Once released into the cytoplasm, CCVs undergo rapid uncoating, mediated by ATP-dependent chaperones such as Hsc70 and auxilin, preparing vesicles for downstream trafficking.

Key Receptor Types

Receptor-mediated endocytosis relies on specialized membrane receptors tailored to distinct physiological needs. Low-density lipoprotein (LDL) receptors regulate cholesterol homeostasis by binding circulating LDL particles, ensuring efficient cholesterol delivery for membrane synthesis and hormone production. Mutations in the LDL receptor gene, as seen in familial hypercholesterolemia, impair uptake, leading to elevated plasma cholesterol and atherosclerosis.

Transferrin receptors mediate iron uptake by binding transferrin, an iron-carrying glycoprotein. Once internalized, the acidic environment of early endosomes releases iron ions for incorporation into hemoglobin, enzymes, and other proteins. Disruptions in transferrin receptor function can contribute to anemia or iron overload disorders.

Epidermal growth factor (EGF) receptors regulate signal transduction and cellular proliferation. Upon ligand binding, they initiate intracellular cascades that influence growth, differentiation, and survival. Endocytosis of ligand-bound EGF receptors terminates signaling and directs receptors toward degradation or recycling. Dysregulation in this process is implicated in oncogenesis, as excessive EGF receptor activation is a hallmark of cancers such as non-small cell lung carcinoma and glioblastoma. Targeted therapies, including tyrosine kinase inhibitors, aim to modulate EGF receptor activity, underscoring the clinical significance of receptor-mediated endocytosis in disease management.

Sorting In Endosomes

Once receptor-mediated endocytosis delivers cargo into the cell, endosomes serve as sorting hubs, directing internalized molecules to their destinations. Early endosomes receive newly formed vesicles and determine whether cargo is recycled back to the plasma membrane, transported to late endosomes for degradation, or shuttled elsewhere. pH changes, protein interactions, and membrane dynamics ensure precise trafficking.

Cargo destined for recycling is directed to tubular extensions of early endosomes, where it is sorted into vesicles that return to the cell surface. This pathway is crucial for receptors such as the transferrin receptor, which cycles between the plasma membrane and endosomes to maintain iron homeostasis. In contrast, molecules targeted for degradation transition into late endosomes before fusing with lysosomes. This route terminates signaling pathways and degrades obsolete or damaged proteins, preventing accumulation and toxicity. Membrane proteins marked for destruction are tagged with ubiquitin, guiding them into intraluminal vesicles within multivesicular bodies for efficient breakdown.

Altered Pathways In Disease

Disruptions in receptor-mediated endocytosis impair cellular homeostasis, nutrient uptake, and signal regulation. These alterations result from genetic mutations, environmental stressors, or pathogen exploitation of endocytic machinery. Malfunctions can cause receptors to accumulate at the membrane, degrade prematurely, or fail to recycle efficiently, leading to imbalances in cellular function.

Neurodegenerative disorders often involve defective receptor trafficking, affecting neuronal survival and synaptic communication. In Alzheimer’s disease, abnormalities in the endosomal system misprocess amyloid precursor protein (APP), promoting amyloid-beta plaque accumulation. Early endosomal enlargement and trafficking defects precede amyloid deposition, indicating receptor-mediated endocytosis plays a role in disease progression.

Cancer cells exploit endocytic pathways to sustain growth and evade regulation. Altered trafficking of growth factor receptors, such as epidermal growth factor receptor (EGFR), leads to prolonged signaling that drives tumor proliferation. Instead of degrading after activation, these receptors may be excessively recycled, maintaining continuous mitogenic stimulation. This occurs in aggressive cancers such as glioblastoma and non-small cell lung carcinoma, where mutations in receptor trafficking proteins enhance oncogenic signaling. Targeted therapies, including monoclonal antibodies and tyrosine kinase inhibitors, aim to restore normal receptor dynamics by blocking aberrant internalization or redirecting receptors toward lysosomal degradation. Understanding how receptor-mediated endocytosis is hijacked in malignancies provides critical insights into therapeutic strategies.