The 3D Structure of Proteins Flashcards
What amino acid categories are ther?
Charged amino acids which may be subdivided into acidic or basic (negative or positive)
Sometimes the sulphur containing amino acids are a separate group
GLycine is sometimes considered non-polar sometimes it’s a separate group
Histidine is sometimes considered as a charged basic amino acid
What groups does each amino acid property confer?
Carboxyl groups COO- - charged or acidic
Amine groups NH3+ - charged or basic
Secondary amine NH and carbonyl C=O groups- polar
Hydroxyl OH - polar
Hydrocarbon - Non-polar hydrophobic
Properties of a protein also depends upon the amino acid composition
Describe the bonds on a polypeptide
Delocalised electrons of the N-CO makes the bond ridged with the oxygen and hydrogen atoms on opposite side lying in the same plane
The peptide bond is thus a planar structure with the rotational freedom within a polypeptide is found around the alpha carbon, not the peptide bond
The amide C-N bind is relatively rigid (due to its partial double bond characteristic) comprising a planar unit 4 connected atoms ( 6 if you include Ca atom)
However, the adjacent C-C (psi) and N-C (phi) bonds can undergo torsional-rotational motions resulting in folding of the chain
Why is rotational freedom from bonds essential in polypeptides?
Rotational freedom of the bond allows huge variation in the conformation of the peptide chain
This freedom favours the formation of structural arrangement such as alpha helices and beta sheets
Glycine is a special amino acid in that the R group being a hydrogen allows for greater flexibility
The free energy of any conformation is affected by what factors in the molecular environment?
Aqueous or lipid (a membrane)
Other proteins or molecules including salts and their ionic state
Changes in this environment can induce further conformational change for example association with cofactors or binding a ligand
Which bonds provide greater structural stability?
Weak non-covalent bonds have 1/20th strength of covalent bonds
But the overall contribution of non-covalent bonds is significant because non-covalent bonds are far larger in number
List the non-covalent bond occurring in proteins?
Charge or electrostatic attractions:
Falls off exponentially as distance increases, affected by electrostatic environment (aqueous environment)
Hydrogen bonds:
Transient bonds similar in some respects to covalent bonds
Van der Waals attraction- dipole-:
These weak forces occur between two atoms
Determined by their fluctuating charge
Attraction at a close distance is balanced by repulsion due to proximity that is determined by the van der Waals radius of an atom
Van der Waals forces are induced by the proximity of molecules
Hydrophobic interactions:
Water is a polar molecule
Hydrophobic interactions minimise disruption of water network- i.e. the fourth weak force
What covalent bond occurs in proteins?
Disulphide bonds
Disulphide bonds form between side chains of two cysteine residues
Bonds form in an oxidative reaction
The SH groups from each cysteine cross-link
Usually occurs in distant parts of the primary sequence but adjacent in the three-dimensional structure
Can form on the same (intra-chain) or different (inter-chain) polypeptide chains
What disorders can arise from protein misfolding?
The function of the misfolded protein is almost always lost or reduced
Misfolded proteins often have a tendency to self-associate and form aggregates:
Huntingtin Htt (Huntington’s)
Amyloid-beta Ab (Alzheimer’s)
Prion protein (PrP^Sc) Creutzfeldt-Jakob disease and variant CJD
Alpha-synuclein (Parkinson’s disease)
Serum amyloid A (AA amyloidosis)
Islet amyloid polypeptide IAPP (type 2 diabetes)
And many more
Other misfolded proteins result in cellular processing that leads to their degradation include:
Cystic fibrosis
What are the reasons misfolding can occur?
Somatic mutations in the gene sequence leading to the production of a protein unable to adopt the native folding
Errors in transcription or translation leading to the production of modified proteins unable to properly fold
Failure of the folding machinery
Mistakes of the post-translational modifications or in trafficking of proteins
Structural modification produced by environmental changes e.g. heat stress
Induction protein misfolding by seeding and cross-seeding by other proteins
How is it thought that protein misfolding leads to Alzheimer’s?
In Alzheimer’s disease, proteolytic cleavage of Amyloid Precursor Protein (APP) is observed
APP has multiple functions but is involved in G-protein signalling
Cleavage of APP results in a @40 residue peptide beta amyloid
In the intact molecule this anchors the protein in the membrane APP accumulates and mis-folds to form beta sheets
In Alzheimer’s disease the beta-Amyloid peptide accumulates
Mis-folding of this protein results in a planar arrangement and polymerisation
This can form fibrils of misfolded protein (amyloid fibrils)
Beta-amyloid fibres are formed from stacked beta sheets in which the side chains interdigitate
How can protein misfolding leading Cystic fibrosis?
In cystic fibrosis, the most common mutation is a deletion of Phenylalanine at residue 508 of the cystic fibrosis transmembrane conductance regulator (CFTR)
∆F508del leads to misfolding of the protein whilst it is still in the ER
This is recognised by the cellular machinery that identifies and processes misfolded protein
This results in ubiquitination, trafficking to the proteasome and degradation
What are Prions?
Misfolded proteins (PrP^Sc) that interact with other normal proteins (PrP^C)
Through this interaction, they induce misfolding of the normal proteins and polymerisation
Oligomers form fibrils of misfolded protein
This process is reliant upon the concept of energy minimisation ∆G
It is a dynamic process brought about by the interaction of molecules resulting in a more stable aggregated structure
