Cell Surface Proteins

Introduction

Cell surface proteins are proteins that are located on the surface of cells and play a variety of important roles in cellular function. They are embedded within the plasma membrane of cells and can act as receptors, enzymes, transporters, adhesion molecules, and signaling molecules.

Cell surface proteins are involved in many essential biological processes, including cell signaling, cell-to-cell communication, cell adhesion, immune response, and transport of molecules across the cell membrane. They are also important targets for drug development, as they can be used to selectively target specific cells or tissues in the body.Function

Overview

•  Purpose
  • allow cells to attach to each other
    • via different types of cell-cell junctions
  • allow cells to attach to the basement membrane
    • complex interaction between cells and supporting matrix
    • two divisions
      • basal lamina – provides attachment for most types of epithelium
        • composition
          • type IV collagen
          • laminin
          • heparan sulfate
      • reticular lamina – supports lymphoid and adipose tissues
        • composition
          • type III collagen (reticular fibers)
• Types of molecules
  • cadherin
    • structure
      • calcium dependent
      • binds cadherin dimer on another cell extracellularly
      • binds actin intracellularly (via catenin)
    • function
      • ↑ cell-cell binding
        • cadherin receptor ↓ regulated in cancer metastasis
  • selectin
    • calcium dependent
    • function
      • binds carbohydrates in cell-cell interactions
    • subtypes
      • L-selectin
        • on leukocytes
        • L-selectins have Sialyl-Lewis glycoproteins as ligands
      • P-selectin
        • on platelets and endothelial cells
      • E-selectin
        • on endothelial cells
        • binds leukocytes strongly
          • ↑ expression on surface during acute inflammatory response
            • stimulated by TNF-α
      • LAD II is caused by a defective selectin ligand
        • impaired interaction with E- and P- selectins on endothelium
          • causes a rolling defect
          • presents with recurrent bacterial infections with psychomotor and mental retardation
  • integrin
    • structure
      • calcium-independent
      • transmembrane
      • binds fibronectin and laminin extracellularly
      • binds actin intracellularly
    • function
      • binds leukocytes
        • neutrophilic attachment in adhesion via an integrin LFA-1
        • defective in leukocyte adhesion deficiency (LAD) type I
          • interaction with ICAM and VCAM impaired
          • causes an adhesion defect
          • presents with recurrent bacterial infections and delayed loss of umbilicus postpartum
      • bind to laminin in ECM
• integrin receptor ↑ regulated in cancer metastasis

Types of Cell-Cell Junctions

• Tight junctions
  • aka zonula occludens
  • structure
    • zona occuldens (ZOs) 1, 2, 3
    • claudin proteins
    • membrane spanning proteins
      • bind cell_A actin intracellularly on one end
      • bind cell_B actin intracellularly on opposite end
  • location
    • apical end of epithelial cells
  • function
    • prevent diffusion
    • create cell membrane polarity
• Adherens junctions
  • aka zonula adherens
  • structure
    • cadherin proteins
      • Ca²⁺-dependent adherin = cadherin
  • location
    • belt around cell
      • below tight junction
• Desmosomes
  • aka macula adherens
  • structure
    • cadherin proteins
      • link between two cells
      • attach to intermediate filaments
    • keratin and desmoplakin proteins
  • location
    • distinct sites
  • function
    • rivets
    • gives strength to junction between cells
  • clinical importance
    • pemphigus vulgaris
      • pathophysiology
        • auto-IgG against desmosomal proteins in keratinocytes
        • type II hypersensitivity
      • presentation
        • painful, flaccid vesicles form on skin and oral mucosae
          • located above basal layer
          • because it is above the basal layer the blister is weak
            • positive Nikolsky sign
              • outer epidermis separates with gentle rubbing
        • acantholysis
          • loss of connection between cells
        • post-inflammatory hyperpigmentation
      • treatment
        • immunosuppression (corticosteroids)
• Hemidesmosomes
  • structure
    • composed of integrins
    • bind type IV collagen, fibronectin, laminin of basal lamina extracellularly
    • bind intermediate filaments intracellularly
  • function
    • like a desmosome but instead of attaching cell-to-cell it attaches cell-to-basement membrane
      • “half of a desmosome”
  • clinical importance
    • bullous pemphigoid
      • pathophysiology
        • auto-IgG against basement membrane hemidesmosomes 
        • type II hypersensitivity
        • can be drug-induced
      • presentation
        • wide distribution of skin blisters
          • unlike pemphigus vulgaris → does not involve oral mucosae
          • vesicles below the epidermis
          • stronger vesicles
            • negative Nikolsky sign
        • NO acantholysis
      • treatment
        • immunosuppression (corticosteroids)
    • cancer
      • metastasis involves timely ↓ regulation of hemidesmosomal proteins
• Gap junctions
  • structure
    • pores formed by 6 connexon proteins
  • function
    • allow direct passage of small molecules from one cell to another
      • e.g. Ca²⁺, cAMP
    • role in electrical and metabolic signalling
• no role in strength 

Function

Cell surface proteins play a wide variety of functions in cellular and organismal biology. Here are some of the main functions of cell surface proteins:

1. Cell-cell adhesion: Some cell surface proteins, such as cadherins, integrins, and selectins, mediate the adhesion of cells to one another, thereby maintaining the structural integrity of tissues and facilitating cell migration during development and wound healing.
2. Cell signaling: Many cell surface proteins, such as G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), act as receptors for extracellular ligands, such as hormones and growth factors, and transmit signals into the cell to regulate cellular processes such as gene expression, cell growth and differentiation, and metabolism.
3. Transport of molecules: Some cell surface proteins, such as ion channels and transporters, facilitate the movement of ions, nutrients, and other molecules across the cell membrane, which is critical for maintaining cellular homeostasis and supporting cellular functions such as nerve impulse transmission and muscle contraction.
4. Immune response: Cell surface proteins play a key role in the immune response by mediating the recognition and response to foreign antigens. For example, the major histocompatibility complex (MHC) proteins present antigens to T cells, which then activate the immune system to target and eliminate pathogens.
5. Cell-matrix adhesion: Cell surface proteins such as integrins mediate the adhesion of cells to the extracellular matrix, which provides structural support to tissues and also plays a critical role in cell signaling and proliferation.
6. Cell migration: Some cell surface proteins, such as selectins and integrins, facilitate cell migration by mediating interactions between cells and the extracellular matrix, or by interacting with other cell surface proteins to promote cell motility.

Overall, the functions of cell surface proteins are diverse and essential for many biological processes. The study of these proteins is an important area of research with implications for many fields, including cancer biology, immunology, and drug development.

Studies

The study of cell surface proteins is a critical area of research in cell biology and biomedical sciences, with implications for a wide range of fields, including drug discovery, cancer biology, immunology, and neuroscience. Here are some of the main areas of research related to cell surface proteins:

1. Protein structure and function: One important area of research is to understand the structure and function of specific cell surface proteins, such as GPCRs and ion channels. This involves using techniques such as X-ray crystallography, cryo-electron microscopy, and functional assays to elucidate the molecular mechanisms by which these proteins interact with ligands and transmit signals into the cell.
2. Receptor signaling: Another area of research is to understand the signaling pathways that are activated by cell surface receptors, such as RTKs and GPCRs. This involves studying the downstream effectors of these pathways and their role in regulating cellular processes such as proliferation, differentiation, and metabolism.
3. Cell adhesion and migration: Researchers also study the role of cell surface proteins in cell adhesion and migration, which is critical for processes such as tissue development and wound healing. This involves studying the interactions between cell surface proteins and the extracellular matrix, as well as the downstream signaling pathways that regulate cell motility.
4. Drug discovery: Cell surface proteins are important targets for drug discovery, as they can be used to selectively target specific cells or tissues in the body. Researchers are actively developing new drugs that target cell surface receptors, transporters, and other proteins for the treatment of diseases such as cancer, cardiovascular disease, and neurodegenerative disorders.
5. Immunology: Cell surface proteins play a key role in the immune response, and researchers are studying how these proteins interact with the immune system to mediate the recognition and response to foreign antigens. This includes studying the MHC proteins and other cell surface proteins involved in antigen presentation and T cell activation.

Overall, the study of cell surface proteins is a rapidly evolving field with many exciting opportunities for research and discovery. Advances in technologies such as genomics, proteomics, and imaging are enabling researchers to better understand the structure and function of these proteins and their role in health and disease.

Check out USMLE Step 1 Mastery: Comprehensive Course and Lecture Notes.