Please enable JavaScript.
Coggle requires JavaScript to display documents.
Protein Structure - Coggle Diagram
Protein Structure
Folding
-
-
Bonds
-
Peptide Bonds
This bonds behaves somewhat like a planar double bond, the portions on either side of the peptide bond can be orientated in either trans or cis configuration relative to peptide bond
In the bond, the carbonyl carbon and amide nitrogen and atoms directly bonded to them all lie in fixed plane, little rotation about the peptode bond itself is possible
teh only flexibility in a polypeptide chain is the rotation of fixed planes of adjacent peptide bonds wiht respect to one another about the amino nitrogen bond and carbonal carbon bond
Levinthal paradox- assume each carbon can have one of three bond angles for 100 amino acids then th etime it takes for the formation of the correct structure is 1.6x10^27 years, so the searching process is not random
-
Cells use PPIases to catalyses cis/trans isomerisations so that Pro in folding protein forms the proper isomer, these isomerisations can drastically alter protein structure
-
Chaperones
total cytosolic protein concentration can be 300mg/ml in mammalian, these high concentrations favour formation of aggregates by increasing chances a nascent protein will encounter proteins prior to folding and so aggregate into awter-insoluble mass due to hydrophobic effect
Intrinsically disordered proteins are less likely to form deleterious aggregates as have fewer hydrophobic side chains, whereas newly synthesised have high risk as not yet properly folded
95% of proteins in cells are in native control, without chaperones the cell would waste too much energy to destroy aggregates
chaperones facilitate folding by preventing aggregation yb binding to polypeptide or sequestering it from other partially unfolded proteins so nascent protein has time to correctly fold
They help fold newly made proteins or refold misfolded or unfolded proteins; sometimes the protein fails to fold so the chaperones re-engage for additional cycles
-
They bind to client proteins and use a cycle of ATP binding, hydrolysis and exchange to induce conformational changes. ATP used for enhanced binding, switching own configuration, optimise folding and returning to initial state
2 families
Molecular chaperones
They bind to a short segment of protein and stabilise unfolded/partially folded proteins and prevent aggregation and degradation
Bind to nascent cahin as being synthesised, as leaving ribosom
2 types
Hsp70
-
-
co-chaperone accessory proteins (DnaJ/Hsp40) stimulate ATP hydroylsis (increase hydrolysis rate 100-1000 times the induces a large conformational change in substrate binding domain causing closed conformation, in which the substrate is tightly locked in
exchange of cytosolic ATP for bound ABP stimualted by otehr proteins (GrpE/BAG1) converts it back to open conformation, releasing the substrate and freeing it to continue folding
-
Hsp90
-
-
-
unlike Hsp70, they function as a dimer in a cycle. Rapid ATP binding leads to conformational change in which nucleotide binding domains and substrate binding domains move together into a closed conformation
The closed conformation means the client protein may undergo folding, binding of clinets to Hsp90 occurs at different points
ATP hydrolysis causes change that may include highly compact form, client folding, client protein release adn additional folding of unbound client. ADP then released
Chaperonins
these are huge cylindrical supramolecular assemblies with a centre of chambers in will protein enters; the chamber allows folding and is formed from 2 rings of olgiomers
2 groups
Group I
found in prokaryotes, chloroplasts adn mitochondria
composed of 2 rings each with 7 subunits and each ring is a folding chamber into which an unfolded protein enters
GroEL/GroES
-
a misfolded protein enters and the second chamber is then blocked by a GroES lid, each ring of 7 GroEL subunits binds 7 ARPs, hydrolyses them to set coordinated GroES and protein binding, folding and release
-
the polypeptide remains in chamber capped by lid adn undergoes folding until ATP hydrolysis induces binding of ATP na da differenct GroES to the ring
this binding causes GroES led and ADP to be released which opens the chamber and lets out folded protein
Group II
-
They have 8-9 homomeric or heteromeric subunits in each ring and lid funciton is incorporated into those subunits
-
TriC
ATP binding and hydrolysis in presence of bound client protein leads to closing of the lid and folding of client in sequestered environment withing the folding chamner
-
Misfolding diseases
-
many proteins can each aggregate into amyloid fibrils that have a bross B-sheet, where each strand is nearly perpendicular to the long axis and 2 long B sheets pack closely together and twist aroufn each other to form protofilaments which then assemble together int amyloid fibrils
amyloids are associated with amyloidosis diseases each characterised by presence of filamentous plagues in deterioratign brain
in Alzheimer's a hyperphosphorylated form of protein tau forms twisted fibres called tangles which are relatively short, water-soluble protofilaments or long insoluble fibrils
Quaternary Structure
can be dimers, trimers, tetramers (icosahedral are found in viruses)
-
it is a combination of either homomeric (identical) or heteromeric (different) protein subunits held together by noncovalent bonds
sometimes the individual monomer subunits cannot function unless assembled but sometimes when multimeric protein assembly permits proteins that act sequentially in a pathway to increase their efficiency
supramolecular complexes
-
-
the capsid that encases the nucleic acids of a viral genome and cytoskeleton are structural examples
A molecular machine responsible for synthesising mRNA, it involves RNA polymerase and at least 50 additional components
The nuclear allows access of macromolecules to pass nuclear membrane and is composed of multiple copies of 30 distinct proteins with 50 MDa mass
Biomolecular condensates
-
unlike supramolecular components their components fo not have a fixed stoichiometry, can vary in size, nor have fixed quaternary structural arrangement
-
the capacity of a protein to form a condensate depends on structure, concentration and conditions
they contain multiple domains that have ability to bind to regions of other proteins or nucleic acids, and when a protein does bind it oligomerises at the oligomerisation sites
examples
Wnt signalling
-
fluorescently labelled version of D. melanogaster APC2 and Axin were expressed in mammalian cells and assembled inot spherical condensates
-
-
Amino Acids
Types
Polar- Tyrosine, tryptophan, asparagine, glutamine. cytesine, serine, theronine
nonpolar- glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine
charged- histidine, asparate, glutamine, lysine
Tyrosine, tryptophan and phenylalanine absorb and give uniques UV spectrums
-
pH alteration
pKa
-
it is protonated when pH is less than pH, since it is surrounded by protons
-
Modifications
-
modification by phosphorylation, which makes it negative
-
Primary Structure
-
-
It is the linear covalent arrangement of amino acid residues that compose it, linked by peptide binds
Oligopeptides are short chains of amino acids linked by peptide bonds and longer chains are refered to as polypeptides (200-500 residues)
Can be covalently modified by phosphorylation of glycosylation which can alter the mass of those residues
Secondary Structure
Alpha helix
hydrogen bonds
-
all H-bonds in same orientation which creates a dipole so N-terminus is positive and C-terminus negative
the carbonyl oxygen atom of each peptide bond is H bonded to the amide H atom of the amino acid 4 residues farther in C terminus direction
all the backbone amino and carboxyl groups are H bonded to one another (conferring substantial stability) except at beginning and end of helix
-
Pro (because of covalent bonding of amino group to carbon in side chain prevents stabilising through normal hydrogen bonding) and Gly are unable to form helices
side groups
-
-
Hydrophilic helices have polar side chains extending outward on the outer surfaces (so they can interact with the aqueous environment)
Hydrophobic helices with nonpolar side chains tend to be buried within the core of the folded protein
-
Beta Sheet
-
stabilised by hydrogen (between the carbonyl O atom of each residue in 1 B strand and amide H atom of a residue in an adjecent B strand)and peptide bonds
-
-
can curve around and form a cylinder, called a beta barrel, when these proteins are embedded in membranes the cylindrical beta sheet can form a hydrophilic central pole through which ions and small molecules may flow
Beta turn
-
often have Pro and Gly, the lack of large side chain in Gly and presence of a built in bend in Pro allows tight bending
-
the first and fourth residues are usually less than 0.7nm apart and those residues are often link ed by a H bond
Parts of a polypeptide that don't form secondary structures but have a wall defined, stable shape have an irregular structure. The areas of highly flexible parts with no stable, fixed 3D structure have random coil
Structural motifs
-
-
some are stable after being isolated from the rest of the protein but others do not form thermodynamically stable structures in the absence of other portions of the protein
Coiled-coil
-
many fibrous proteins and transcriptional factors assemble into dimers or trimers by using this motif
They bind as each helix has an alipathic side chain strip that interact with a similar strip in the adjacent helix so sequestering hydrophobic groups away from water and stabilising the assembly of multiple independent helices; the hydrophobic strops along only one side because the primary structure of each helix is composed of heptad repeats (in which the side chains of first and fourth residues are alipathic and others are often hydrophilic)
EF HAnd
-
Ca2+ ion binds to oxygen atoms in conserved residues in the loop when the concentration of Ca2+ in the cell is high enough, the binding can induce a conformational change in the protein
Tertiary structure
Categories
-
Fibrous
They are large, elonagated stiff molecules
some are composed of a long polypeptide chain comprising many tandem copies of a short amino acid sequence motif that forms a single repeating secondary structure
often made up of helical polypeptide chains like a helices, triple helices and helical coil coils with multiple strands
-
Integral membrane
-
membrane spanning domain comprises of one or more roughly 20 residue long a helices and some Beta barrels
Disordered
meaning that they do not form thermodynamically stable structures, and they are exceptionally flexible in conformation
phosphorylation of the disordered C terminal domain of RNA pol II, composed of multiple repeats of 7 amino acid sequence contain Pro, Thr and Ser an dregulates mRNA synthesis
Sometimes the entire polypeptide chain is disordered, so these proteins do no t have a well ordered structure in their native state, these proteins are called intrinsically disordred proteins. These usually serve as signalling molecules, activity regulators or as scaffolds for multiple proteins, small molecuels and ions
Intrinsically disordered proteins adn disordered regions can be identified by tests of protease sensitivity (since they usually exhibit greater protease sensitivity) and by spectroscopy
The segments arise when they are richer in polar amino acids, proline and poorer in hydrophobic residues
In some cases an intrinsically disordered protein (or region) can transition into a highly ordered structure
Comparison
-
the greater the similarity in sequences of 2 polypeptide chains the more likely they are to have similar 3D structures and function
Proteins that hav a common ancestor are referred to as homologs, evidence for thsi is similarity in sequences
generally thought that proteins with about 30& sequence identity (exact amino acid matches) are likely to have similar 3D structures
Domains
-
3 classes
functional domain
region of protein that exhibits particular activity characteristic of that protein even when isolated from rest of protein
-
-
structural domain
is region of about 40 or more amino acids arracnged in single, stable and distinct structure often comprising one or more secondary structures
-
distinct domains can be linked together by spacers to form a larfe multidomain protein (like hemagglutinin)
-
they can be reognised on proteins whose structures have been determined by x-ray crystallography or NMR analysis or electron microscopy
EGF domain
present in several proteins- small, soluble peptide hormone that binds to cells in the embryo and skin of adults
generated by proteolytic cleavage between repeated EGF domains in EGF precursor protein anchored in plasma membrane
found in tissue plasminogen activator (dissolves blood clots), Neu protein (embryonic differentiation), Notch protein (receptors in membrane for development signalling)
-
Interactions
stabilised primarily by hydrophobic interactions between nonpolar side chains with van der Waals interactions and H bonds involving both polar side chains and backbone amino and carboxyl groups
because the interactions stabilising tertiary structures are often weaker than secondary structure, the tertiary is not rigidly fixed but can continually fluctuate
Bonds
Disulphide bonds can covalently link regions of the proteins which restricts protein flexibility and increases stability
protein solubility can increase as amino acids with charged hydrophilic polar side chains tend to be on outer surfaces and interact with water