Download five structure-function classes of membrane proteins

FIVE STRUCTURE-FUNCTION CLASSES
OF MEMBRANE PROTEINS
I.
Transport Proteins
A.
Occlusion transporters:
Occlusion transporters bind substrates stereospecifically, one molecule per binding site.
The protein pathway contains at least 7 transmembrane helices (TMH’s). The largest family of occlusion
transporters is the 12 TMH family with several hundred examples. A web site that has a comprehensive
list of all the known transport proteins (over 2000 from some 350 species ) is that of Milton Saier.
(www-biology.ucsd.edu~msaier/transport/titlepage2.html) It is attached. They are listed so that each
transport protein is backed up by a description of the system and references.
Transport proteins contain at least two conformations with equivalent energy. Each contains a substrate
binding site, one facing each side of the bilayer.
They include active transporters (pumps, antiporters, symporters) and passive transporters. The timescale of
their activity is ~1ms. This is in contrast to the channels below which conduct transport on a 1µs
timescale.
B.
Channels:
Channels transport pulses of specific ions across bilayers. Each open event allows many ions to flow through
the channel.
Channels typically have 4-6 subunits. Each subunit has 4-6 transmembrane helices.
II.
Membrane-Bound Enzymes
A.
Membrane-associated enzymes: Water-soluble enzymes bound to the membrane by
protein-protein binding. Rarely do they bind to membrane lipids. Solubilized by high salt
concentrations.
B.
Hydrophobic-tail enzymes:
Water-soluble enzymes anchored to the membrane by a TMH. The hydrophobic TMH may assume an antiparallel pleated sheet folding back on itself. (cytochrome b5)
C.
Lipid-anchored enzymes:
Water-soluble enzymes anchored to the membrane by covalent attachment to a lipid. On the cytosol side the
lipids include N-myristoyl, S-palmitoyl, S-geranylgeranyl, S-farnesyl or on the ektolayerside,
phosphatidyl-inositol glycan (GPI). The signals for these attachements are in the amino acid sequence.
D.
Hydrophobic-active-site enzymes:
The active site of the enzyme is in the low dielectric of the bilayer. The conformation of the active site is not
based on water of hydration which is true of all other membrane bound enzymes. The substrates for
these enzymes are lipids. (e.g., desaturases).
III. Membrane-Bound Networking Proteins:
A new grouping of known membrane proteins. The biological function of these proteins is accomplished
through specific protein-protein binding motifs.
A.
Membrane-bound networking (cytoskeletal) proteins:
Water-soluble proteins bound to the membrane by protein-protein binding to trans-membrane proteins. They
may be solubilized by high salt concentration. (Spectrin, clathrins, intermediate filaments, etc.)
B.
Membrane-bound ektolayer networking proteins:
Water-soluble proteins bound to the ektolayer surface of the membrane by protein-protein binding to transmembrane proteins. They may be solubilized by high salt concentrations. (Cadherins, etc.)
C.
Single-crossing networking proteins:
Referred to as "receptor proteins" they actually expand cytoskeletal activities through the membrane.
These proteins allow cell-cell communication via the cytoskeleton and permit hormones and other chemical
signals to manipulate the cytoskeleton. The purpose of the TMH is to connect in 2-dimensional space a
protein-protein binding domain on one side of the bilayer to a protein-protein binding domain on the other.
1.
"Dimerizing" networking proteins:
These communicate through the bilayer by forming a dimer. Two monomers bind to an ektolayer signal
molecule (agonist) forming a transmembrane dimer. A new protein-protein binding site is created on
the endolayer side of the bilayer. Recognition of this binding site by cytoskeletal elements would
constitute the signal. [EGF receptors, aspartyl chemotaxis receptor (TAR), etc.]
2.
"Pattern-forming" networking proteins:
These communicate through the bilayer by forming a pattern. The single-crossing receptors bind to a
large particle (VLDL, virus, etc.) containing multiple copies of the agonist. The receptors aggregate to
form a pattern on the membrane. This pattern is on both sides of the membrane. The pattern on the
endolayer side is recognized by cytoskeletal elements. The nucleation of a new cytoskeletal structure
results (clathrin coated pits, etc.).
IV. G-protein Receptors or Heptahelicals:
This second class of receptor proteins always contain 7 TMH’s. They signal to G-proteins (which are
membrane bound enzymes anchored by lipid anchors. The signalling mechanism is unknown. The action
relates to the low dielectric of the bilayer because they always bind the signal in the low dielectric of the bilayer.
Although they ultimately bind the α-subunit of the G-protein this does not explain why they have a large
intramembrane domain. The binding is on the aqueous surface. It also does not explain how the receptor
provokes GDP-GTP exchange. In summary the basis for the structure-function relationship is not clear.
V.
Fusion Proteins:
Fusion proteins facilitate the fusion of apposed bilayers. It is not clear that this group is legitimate class
of membrane proteins. Only one fusion protein is known to be a membrane protein to date, the viral
haemogluttinins. These proteins are single-crossing proteins that contain a hysrophobic pop-out domain within
their water-soluble domain. (examples are haemagluttinin, the SNAP/SNARE system, etc.)
The proteins that provoke fusion of eukaryote endosomes and synaptosomes appear to be cytosolic
soluble proteins that bind to single-crossing proteins. Aggregates form in order for fusion to occur. ATPbinding sites are present (and necessary for fusion) in these complexes. The complexes also contain singlecrossing proteins.