LS3-7-10 - Lecture 7 Finnish Women of Achievement Leena...

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Unformatted text preview: Lecture 7 Finnish Women of Achievement: Leena Peltonen-Palotie (1952-2010) UCLA Human Genetics 1998-2002 Protein Families Protein Domains Protein Modifications Allison: p83 p85-92 Sickle Cell Anemia •  Due to mutation in β-globin gene E6V mutation Host Genetics and Resistance to Malaria Overlapping distribution of P. falciparum malaria and Sickle Cell Anemia Plasmodium falciparum malaria Sickle Cell anemia Red Blood Cell membrane deformation leads to reduced parasite replication WT/WT WT/SC - Heterozygote advantage SC/SC Protein Families •  Proteins related in primary amino acid sequence and 3D structure •  Common ancestor (homologous) Hemoglobin and Myoglobin - oxygen carriers in vertebrates. O2 is bound to a non-protein group termed Heme. Heme enables hemoglobin to pick up O2 from the lungs and release it in tissue. Heme gives blood its red color. Hemoglobin- In red blood cells. CO2 and H+ are allosteric effectors. They bind at sites distal from the O2 binding site and promote the release of bound O2. Myoglobin - located in muscle and provides a reserve supply of oxygen. Myoglobin is not an allosteric protein. The globin protein family Similarity (Identity) between the amino acid sequences of myoglobin and α-globin Myoglobin α-globin 35/141 = 25% Amino acid similarity – a vertebrate protein AA conservation Identical Conservative substitution Multiple sequence alignment – Globin Family Sequence logo – Globin Family Similarity, Phylogenetic trees, and Homology Ortholog - Separated by speciation event, e.g. α-globin Paralog – duplication within a genome, e.g. α/β-globin, globin/myoglobin Homolog - derived from a common ancestor Structural domains •  Part of the polypeptide chain that can fold independently into a compact stable structure •  ~100 AA (25-500) •  Large proteins may have many domains •  Domains are often associated with different functions Structural (composition) •  •  •  •  •  •  Globular Rod/Stalk Acidic Basic Helix-turn-helix Greek key •  •  •  •  Functional Membrane spanning DNA binding Nucleotide binding Kinase Domains in a protein can be defined based on their function (& composition) •  Binding site –  region that interacts with another molecule (ligand) through non-covalent interactions •  Dimerization region •  Active site –  region where two different polypeptides interact –  region where catalysis takes place on enzyme •  Regulatory site –  binding site for molecule which affects activity of protein (frequently through conformational changes). Structural motifs •  Small domains also referred to as motifs, e.g. Zinc Finger (DNA-binding domain) 23 6 6 19 19 3 3 23 Structural motifs & Sequence motifs •  Zinc Finger •  C-X2-C-X12-13-H-X3-H •  C-X2-H-X12-13-H-X3-H Protein functions are determined by their combination of domains •  Many proteins have multiple domains, each with specific functions –  Regulatory transcription factor –  Catabolite Activator Protein •  cAMP binding domain •  DNA binding domain DNA-binding domain Coiled Coil Interaction domains between proteins e.g. Leucine zipper of yeast transcription factor GCN4 Leucine every 7th AA CAP binds to DNA as a dimer: two polypeptides held together by a coiled-coil interaction cAMP-binding DNA-binding Fig 5-18 EGF = Epidermal Growth Factor TPA (tissue plasminogen activator) is a protease that is injected into a heart attack victim to dissolve blood clots. Extracellular proteins are frequently stabilized by covalent linkages •  Disulfide bonds can form between nearby cysteine residues •  Cytosolic proteins are exposed to high concentrations of reducing agents and are not found covalently linked Processing •  removal of peptide segments •  commonly seen in proteins that are activated in response to specific conditions (hormones) or in specific locations (proteases) Proteins are frequently modified covalently after their synthesis. •  Chemical modification •  Acetylation [CH3-CO-] •  Acetyl group can be added to the N- or the C-termini or internal N-lysyl groups Acetylated N-terminus Acylation Modification of a protein by lipids A protein may be anchored to membrane after the protein is attached with lipid molecules, such as farnesyl group, palmitate, or myristate groups. Protein methylation Asymmetric Arginine Symmetric Phosphorylation Phosphate can replace the OH in serines, threonines and tyrosines Proteins are often glycosylated in eukaryotic cells Simple to complex Carbohydrate groups can be added to the side chains of asparagine, serine, threonine or hydroxylysine Eukaryotic Cell Glycosylation occurs in the Endoplasmic Reticulum Proteins can be modified by covalentlyattached proteins in eukaryotic cells Ubiquitin •  Degradation SUMO •  Localization Carboxyl linkage to Amino group of Lysine N ...
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