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Structural Basis for Ligand-Receptor Recognition and
Dimerization
Moosa MohammadiDept. of PharmacologyMedical Science Building, 4th Floor, Rooms 425, [email protected]
In multicellular organisms, the decision a cell has to make whether to divide, to differentiate or to die is controlled by ligands (growth factors, hormones) that circulate outside of the cell. These ligands in order to transmit their signals must interact with cell surface receptors that possess
enzymatic activity known as protein kinase activity.
Nucleous
Plasmamembrane Barrier
Ligands
Covalently linkedAssociatedkinase
kinase
ATP
PP
P P
ATP
1. Inactive receptor monomers 2.Trans-autophosphorylation
3. Active phosphorylated receptor dimer
Early experiments suggesting that receptors undergo
dimerization
•Truncated receptors lacking the cytoplasmic domain inhibit signaling.
•Transmembrane helices are interchangeable betweendifferent receptors.
•Antibodies against the cytoplasmic domain activate the kinase domain.
•Growth Hormone (GH) Receptor
•Erythropoietin (EPO) Receptor
•Bone Morphogenic Protein (BMP) Receptor
•Vascular Endothelial Growth (VEGF) Receptor
•Nerve Growth Factor (NGF) Receptor
•Fibroblast Growth factor (FGF) Receptor
Ligand-Receptor Systems
• Large family of single-pass transmembrane receptors.
• Receptors bind polypeptide ligands: mediators of cell growth, differentiation and immune responses.
• Cytoplasmic domain does not contain intrinsic protein tyrosine kinase activity - associated with Jak tyrosine kinases.
Cytokine Receptors
• GH stimulates the growth and metabolism of muscle, bone and cartilage cells.
• GH is a member of the 4-helix bundle family.
• The active form of GH is a monomer. Stoichiometry of binding is 1:2 GH-GHR.
Activation Through Binding of a Monomeric Ligand – Growth Hormone
Activation Through Binding of a Monomeric Ligand – Erythropoietin (EPO)
• EPO is a haematopoietic cytokine required for differentiation and proliferation of precursor cells into red blood cells.
• Like GH, EPO is monomeric and belongs to the 4-helix bundle family.
• EPO binds to its receptor (EPOR) with a stoichiometry of 1:2 EPO-EPOR.
• Bone morphogenic proteins (BMPs) belong to the Transforming Growth Factor (TGF superfamily of ligands which includes TGF activins/Inhibins and GDFs.
• BMPs regulate bone and cartilage formation in adults and are also involved in central steps in early embryonic development.
•BMPs are dimeric ligands and have the characteristic “Cystine Knot “ motif found in other members of TGFfamily.
• The receptors for TGFfamily of ligands are transmembrane receptors with intrinsic serine/threonine kinase activity.
Activation of a Receptor Serine/Threonine Kinase – Bone Morphogenic Protein (BMP) Receptor
• Large family of single-pass transmembrane receptors.
• Receptors are predominantly for growth factors but also for insulin.
• Cytoplasmic domain contains intrinsic protein tyrosine kinase activity.
Receptor Tyrosine Kinases
• VEGF is a mitogen that is highly specific for endothelial cells.
• VEGF is a potent angiogenic factor involved in the development of the vascular system and also in tumor angiogenesis.
• VEGF is a covalent (disulfide-linked) dimer.
Activation Through Binding of a Dimeric Ligand – Vascular Endothelial Growth Factor
• NGF is a member of a family of neurotrophins which also includes brain-derived neurotrophic factor (BDNF), NT-3, NT-4/5 and NT-6.
• NGF mediates neuronal differentiation and survival.
• These neurotrophins are non-covalent dimers, members of the cystine knot family.
Activation Through Binding of a Dimeric Ligand – Neurotrophic Growth Factor