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Section 6.doc

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Department
Biology
Course
Biology 2382B
Professor
Prof
Semester
Winter

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Section 6: Membrane Proteins Three types of membrane proteins: 1. Integral 2. Lipid-linked 3. Peripheral Integral Membrane Proteins - also called transmembrane proteins, span a phospholipid bilayer and comprise three segments - the cytosolic and exoplasmic domains have hydrophilic exterior surfaces that interact with the aqueous solutions on the cytosolic and exoplasmic domains - the segments resemble water-soluble proteins in their amino acid composition and structure - the transmembrane domains consist of one or more alpha helices or of multiple beta strands α-Helices - alpha helices are approximately 20-25 amino acids, Arg and Lys (charged AA’s) near cytosolic side interact with polar head groups - a single alpha domain is sufficient to incorporate an integral membrane protein into a membrane, however many proteins have more than one alpha helix domain - The predicted length of such an alpha helix is just sufficient to span the hydrocarbon core of the bilayer - The helices in many cells are perpendicular to the bilayer, but in some the helices transverse the membrane at an oblique angle Lipid-Anchored Membrane Proteins - bound covalently to one or more lipid molecules - The hydrophobic segment of the attached lipid is embedded in one leaflet of the membrane and anchors the protein to the membrane - The polypeptide chain itself doesn’t enter the bilayer - Proteins anchored to membrane by lipophilic adduct - Acylation of Gly residue of protein - Prenylation of Cys residue of protein - Glycosylphosphatidylinositol (GPI) anchor (exoplasmic) - Acylation attaches through N-terminal Gly residue - Prenylation attaches Cys residue at or near C terminus - In these lipid proteins the lipid hydrocarbon chains are embedded in the bilayer, but the protein itself does not enter the bilayer - The anchors used to insert proteins at the cytosolic face are not used for the exoplasmic face and vice versa - One group of cytosolic proteins are anchored to the cytosolic face of a membrane by a fatty acyl group covalently attached to an N-terminal gylcine residue - Retention of such proteins at the membrane by the N terminal acyl anchor, called acylation may play an important role in a membrane associated function - A second group of cytosolic proteins are anchored to membranes by a hydrocarbon chain attached to a cysteine residue at or near the C terminus - Some of these chains are prenyl anchors built from 5-carbon isoprene units, which are also used in the synthesis of cholesterol - The additional hydrocarbon anchor is thought to reinforce the attachment of the protein membrane - Some cell surface proteins and specialized proteins with distinctive covalently attached polysaccharides called proteoglycans are bound to the exoplasmic face of the PM by a third type of anchor group, GPI - The exact structures of GPI anchors vary greatly in different cell types, but they always contain phosphatidylinositol (PI), whose two fatty acid chains extend into the lipid bilayer just like those of typical membrane phospholipids; PE, which covalently links the anchor to the C terminus of a protein; and several sugar residues - The enzyme phospholipase C cleaves the phosphate-glycerol bond in PLs and in GPI anchors Peripheral Membrane Proteins - don’t directly contact the hydrophobic core of the bilayer - non-covalent bonds; ionic or hydrogen bonds & van der waal forces - Bound either indirectly or via interactions with integral proteins, lipid anchored proteins or directly by interactions with lipid head groups - Can be bound either cytosolic or exoplasmic - Act as adapter proteins to interact with cytoskeletal filaments associated with the cytosolic face (ankyrin and dystrophyn); interactions provide support for various cell membranes, help determine cell shape and mechanical properties and can play a role in communication between the interior and exterior of the cell - Proteins on the outer surface of the PM and the exoplasmic domains of integral membrane proteins are often attached to components of the extracellular matrix or to the cell wall surrounding bacterial and plant cells, providing a crucial interface between the cell and its environment Insertion of Proteins into the Membranes - Topology: orientation of a transmembrane protein - Topogenic Sequences: 1. N terminal (cleaved) sequences, 2. Stop-transfer/membrane anchor sequence (STA), 3. Signal Anchor – internal (uncleaved) sequence (SA) Synthesis of Type I Proteins - all type one transmembrane proteins possess an N terminal signal sequence that targets them to the ER as well as an internal hydrophobic sequence that becomes the membrane spanning alpha helix - the N terminal sequence on a nascent type one protein initiates co-translational translocation of the protein through the combined action of the SRP and SRP receptor - Once the N terminal enters the ER it is cleaved - Once it has been cleaved the protein continues to translate into the ER lumen - Unlike secretory proteins, there is a section of 22 hydrophobic amino acids that will become the transmembrane portion of the protein, when this reaches the translocon, it stops transfer and the rest of the protein is made in the cytoplasm of the cell. - Stop Transfer Anchor Sequence: prevents the continued translation of a protein into the ER. Becomes anchored in the membrane. - 1. N-terminal is cleaved - 2&3. The chain is elongated until the hydrophobic stop transfer anchor sequence is synthesized and enters the translocon, which then prevents the further translation of the protein into the ER - 4.The STA sequence moves laterally between the translocon subunits and becomes anchored in the bilayer - 5. As synthesis continues, the elongating chain may loop out into the cytosol through the small space between the ribosome and the translocon - 6. When translation is complete the ribosomal subunits are released into the cytoplasm leaving the protein to diffuse in the membrane Synthesis of Type II and III Proteins - no cleavable N terminus, but both contain a single internal hydrophobic signal anchor sequence that functions as both an ER signal sequence and a membrane signal sequence - have opposite orientations into the membrane; this corresponds with where there SA sequences are in the translocon - Type II protein SA sequence directs insertion of the nascent chain into the ER membrane so that the N terminus of the chain faces the cytosol, using the same SRP dependent mechanism described for signal sequences. However SA is NOT cleaved and moves laterally between the protein domains of the translocon wall into the bilayer = membrane anchor. The C-terminal is in the ER lumen - Type III proteins the SA is near the N terminus and inserts the nascent chain into the ER, with the N terminus facing the lumen. The SA sequence of type III also acts as a STA by preventing further translation into the ER lumen. Continued elongation of the chain C terminus to the SA/STA sequence proceeds as it does for type I proteins. With the hydrophobic sequence moving laterally between the translocon subunits to anchor the polypeptide in the ER membrane. - Adjacent to the SA sequences there is a group of positively charged amino acids adjacent to one end of the hydrophobic segment. Type II have the (+) charges on the N terminal side of their SA sequence - If there is a positive charge on the protein, then the rest isn’t allowed into the ER. Charges are used to orient things then anchor them to the membrane. Synthesis of Type IV Proteins - Multipass proteins whoe N terminus extends into the cytosol are the various glucose transporters (GLUTs) and most ion-channel proteins - In these proteins, the hydrophobic segment closest to the N terminus initiates insertion of the nascent chain into the ER membrane with the N terminus oriented toward the cytosol; thus this alpha helical segment functions like the internal SA sequence of a type II protein - As the nascent chain following the first alpha helix elongates it moves through the translocon until the second hydrophobic alpha helix is formed - This helix prevents further extrusion of the nascent chain through the translocon until; thus its function is similar to that of the STA sequence from Type I - After synthesis of the first two transmembrane alpha helices, both ends of the nascent chain face the cytosol and the loop between them extends into the ER lumen - The C terminus of the nascent chain then continues to grow into te cytosol as it does in the synthesis of type I and type III proteins – according to this mechanism, the third alpha helix acts as another type II SA and the fourth as another STA sequence - Apparantly once the first topogenic sequence of a multipass polypeptide initiates association with the translocon and topogenic sequences that subsequently emerge from the ribosome are thhreaded into the translocon without the need for the SRP and the SRP receptor < Topogenic sequences are shown in red; soluble, hydrophilic portions in blue. The internal topogenic sequences form transmembrane alpha helices that anchor the proteins or segments of proteins in the membrane. Membrane Transport - Simple Diffusion: only gases, such as oxygen and carbon dioxide and small uncharged polar molecules such
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