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Section 6 - Membrane Proteins.docx

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Biology 2382B
Robert Cumming

Membrane Proteins With the exception of needing phospholipids to form semi-permeable closed compartments, membrane proteins carry out the biological functions of membranes Three types:  Integral o Part of the membrane o When part of the membrane are potentially going through the membrane – their orientation will always be the same  Lipid-linked o Linked to lipids that are already present on the membrane  Peripheral o Proetins that are not directly linked to the plasma membrane, are not binded directly to the membrane – bind to a protein on the plasma membrane and in doing so is linked to it These proteins will always be asymmetric Integral Membrane Proteins  Asymmetric: Specifically oriented – it will ALWAYS be the same orientation!  Three distinct domains: o Cystopalsmic (Hydrophillic) o Transmembrane (Hydrophobic) o Exoplasmic (Hydrophilic)  Transmembrane domain o Hydrophobic secondary or tertiary structures that span the lipid bilayer  Alpha Helicies – a row of amino acids that will span the plasma membrane (must be hydrophobic) (20-25 amino acids)  Arg and Lys (Charged AAs) near cytosolic side interact with polar head groups  Cytosolic side has charged amino acids – very close to the transmembrane domain  Charged amino acids just inside the cytosol  Beta Barrles (Hydrophobic)  These are the two most common hydrophobic structures o Usually the exoplasmic domain is glycosylated – there are sugars added to most of the exoplasmic domains of the transmembrane proteins o Outside of the cell or inside the golgi where these sugars are added  Lipid-linked proteins o Taking proteins and linking them to existing lipids o Plasma membranes with existing lipids and linking proteins to these lipids o These proteins can either be linked on the exoplasmic or the cytosolic face o Exoplasmic face  This has to be done in the Er, golgi or inside of a vesicle Membrane Proteins  There are 3 process that can do this:  Acylation of Gly residue of protein  Prenylation of cys residue of protein  PI anchor formation – Glycosylphophatidylinositol  Once it’s been linked the motility of the lipid itself is emparted onto the protein as well  GPI anchors- ALWAYS exoplasmic – always going to be on the outside of the cell, golgi, ER either or  Always added to a phosphatidylinositol (PI) so you need a PI within that membrane for that to happen  You’re using sugar resudes to link that proteins onto the PI on the exoplasmic surface of a membrane  N-Cam GPI anchor but that cell cel adhedios will not have any cytosolic interacitons – this is because you the GPI anchor means you don’t have any interaction with the inside, there is not domain on the opposite side  CYTOSOLIC  Aceylation  N-terminal glysine residue – for your protein to be ascylated to the surface there must be an N-terminal glycine residue  Prenylation  Attaches Cys residue at or near C-terminus  Opposite of the acylation – this time you’re binding the C-terminal domain Peripheral proteins  Not necessarily physically linked ot the membrane but linked through other proteins  Attached through non-covalent interactions: o Ionic Interactions, hydrogen bonds o Protein protein interactions o Van der waals forces  Cytoskeletal filaments can associate with bilayer through peripheral proteins as can ECM components Insertion of proteins into membranes  These proteins must have hydrophobic domains  GPI has to be exoplasmic  Putting proteins into the plasma membrane – consider the C and N terminal domain (can either be Exo or cytosolic)  The most common one is ones with signal sequences – signal recognition particlse take It into a cell organelle)  There are other ways to get thigns into the membrane though – this is called:  Topogenic sequences Membrane Proteins o A charge and shape that is recognized o Topology – shape o Topogeneic sequences aren’t specific sequences per se but specific shapes and charges o There are 4 topogeneic sequences:  N-terminal cleaved signal sequence (most common one)  Stop-transfer/membrane anchor sequence (STA)  Signal-anchor – internal (uncleaved) sequence (SA)  Hydrophobic C-terminus Tail-anchored proteins- C-terminal domain is the anchor  V-snare and T-snare  Have hydrophobic C-termainla domain  You make the tprotein, you start at the N-terminal domain  All proteins are made in the cytosol  Even if you go to the ER – TRANSLATION OCCURS IN THE CYTOSOL  You make this protein, you make the c-terminal domain and it’s cytosolic – the hydrophobic domain is probablameic in the cytosol so it starts to fold and does weird things (this makes it easy tor ecognize, it’s a topogenic sequences)  It’s recognized by something called get3 – for tail anchoring proteins these hydrophobic c-terminal domain is recognized by Get3 – Get3 takes this to the membrane and with the help of Get1 and Get2 and inserts the c-terminal into the transmembrane domain  This requires ATP , Energy to do that  Does not have an exoplamic domain, only cytosolic and transmembrane domain Synthesis of Type I Proteins  Typical proteinst aht most people think of wwhen dealing with transmembrane –  Have N-terminal signal sequence  Have stop-transfer membrane anchor  Cadherin is a type I for example - start off translation in the cytosol always  Start making the protein – first thing that is made is the N-terminal signal sequence, once made it’s recognized  N-terminal signal sequence is reocgnzied and signal transfer takes it there, the signal sequence means put it into the ER  The ribosome docks with the translocon and starts making this protein through the membrane and into the lumen  The N-terminal goes first and therefore the N-terminal domain becomes exoplasmic  N-terminal signal sequences are cleaved off the mature protein, once in the lumen it’s cut off – a mature Tupe I protein does not have the signal sequence – it’s cleaved off Membrane Proteins  You’re making this protein – I you kept translating it thorugh you would just get a secreted luminal bit  Another topogenic sequence is called a stop-transfer anchor sequence after the N-terminal  This tells it to stop putting the protein into the ER  This stop anchor sequence becomes the transmembrane domain and the c- terminal is left as the cytoplasmic domain Synthesis of Type II and Type III  Have asignal-anchor sequence (Internal)  Orientation determined by positively charged amino acids (kept in cytosol)  No n-terminal signal sequence neds to have signal anchor sequence  You translate the protein until you get the signal anchor – this is what tells it that it needs to be in the ER membrane (it’s hydrophobic)  Does the N-terminal domain get into the exoplasmic domain or the cytosol though?  This all depends on the protein itself  TYPE II  IF between the N-terminal domain and the anchor there are lots of charged amino acids you have basically a charged n-terminal domain o This will lead to it staying in the cytosol  TYPE III  If you have charged stuff between the C-terminal and the signal anchor than you get the c-terminal in the cytosplasm  CANT GE THE CHARGES THROUGH membrane Topogenic sequences – sequences in proteins, topology shape that can be recognized – these are guiding things to the ER Teyp IV – Also requires this internal signal Anchor  Same idea where the protein is slowly translated and as this happens you eventually hit the internal signal sequence that is lodged into the membrane  A repeating process – type I has a secreted signal sequence, end terminal sequence that is cleaved,  Type IV lipid proteins have mulieplte transmembrane domains  The orientation of each one of those transmembrane proteins depends on the charges – you can have an even or odd number of transmembrane domains  You’ll need altering stop transfer and anchor sequences  You end up with a protein that has multiple cytosolic and ER/luminal domains o There are different proteins with different numbers of these transmembrane domains Topogenic Sequences  You should be able to put labels back Membrane Proteins  You should know end terminal signal sequence will be luminal  With Type II or Type III you’ll have signal anchor with charges and that will tell you which side will be luminal and cytosolic  Type IV there are two of them - you have repeating signal anchor and stop transfer topogenic sequences  You go in and out of the membrane and the pattern should make sense o You’re tranlstating in the cytosol and you have to take that growing peptide and either shove it into the ER or keep it in the cytosol o What does the ribosome do?  N terminal is made first and then you hit the signal anchor sequence, depending on the charges you’ll get diffent sides in different places – ALL ABOUT THE CHARGES  Stop transfer anchor sequence will tell you to stop transferring into a place (i.e. the lumen)  Signal anchor sequence tells it to go back in the membrane  ALWAYS NEED TO START WITH A SIGNAL ANCHOR – Type II, III and Four o Wit hType II and III you just have the signal anchor but with type IV you have more going o Signal tells you to go to the ER and stop transfer tells you to stop transferring to the ER - generally these things will alternate EXCEPT at the end when you have the signal anchor puts you into the lemen (because there are no charges) and thus the STA you’ll end at the cytosol o Charges should tell you everything, charges will always tell you cytosol o Signal anchor tells you it’s going to go to the lumen, everything after the signal anchor will go to the lumen o Stop transfer tells you to stop going to the lumen, you always then move into the cytosol Transport Across membranes  Membranes are semi permeable – yo uneed things to help facilitate transport of things across the membrane, the proteins help to do this  Passive Diffusion o Rate of diffusion depends on
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