Lecture notes Year 1 MBChB: Introduction to Medical Sciences (IMS)

PROTEINS

PROTEIN DIVERSITY

Proteome: full set of proteins encoded but not the human genome – not the same as number of genes
 Polymorphism give rise to proteins that differ by one amino acid – functions differently
 Alternative splicing during the maturing process for mRNA can give rise to completely different proteins based
on the same gene
 Modification (e.g. adding sugar) causes difference in the final protein

Known proteins – translation factors, transporters, binding, structural, signalling, receptors, binding and enzymes

Type Disease Cause
Enzyme Haemophilia Defective/absent blood clotting factor
Catalase metabolic reactions Phenylketonuria Absence of phenylalanine hydroxylase (breakdown of
phenylalanine) – causes metabolic problems – babies can end
up with permanent brain damage
Transport/storage Sickle cell anaemia Hb not synthesised correctly
Muscle proteins Duchenne muscular Dystrophin is absent/ineffective – lose ability to use muscle –
Physical movement, dystrophy often wheel chair bound, don’t survive beyond teen years
movement of food in the gut
Communication Type 2 diabetes Insulin receptor is faulty, insulin can’t bind, raised blood
Receptors for hormones and glucose
neurotransmitters
Structure Osteogenesis imperfecta Mutation in type 1 collagen – increases risk of bone fractures
Keratin, collagen Scurvy Poor synthesis of collagen when vitamin C isn’t present to
support that process
Channels/transporters Cystic fibrosis Defective CFTR Cl- channel protein- problems with lungs,
Facilitate movement across digestive system, reproductive system
membranes
Regulation Type 1 diabetes Cells that synthesis insulin have been destroyed so no insulin
Cell division, protein present
synthesis hormones
Immunity Myasthenia gravis Body unintentionally creates antibodies that bind to
Antibodies, self-recognition neurotransmitter receptors- difficulty getting muscles to
respond to neurological signals

AMINO ACID STRUCTURE & PROPERTIES


Properties of amino acids
 Categorising R groups- large/small, aliphatic/aromatic, polar/non-polar,
acidic/basic, sulphur-containing (cysteine & methionine), imino (proline)
 Proline – secondary amine, alpha amino group is covalently bonded to
side-chain
o Makes the C – N very inflexible, limits conformations
 All amino acids have a chiral α-carbon apart from glycine
o This makes amino acids optically active- L-isomer and D-isomer
o L-isomer found in proteins
o An enzyme won’t be able to catalyse a reaction of D or L because different groups wouldn’t sit right in the
active site
 The charge on amino acids with ionisable R groups is pH – dependant
o pKa: pH at which a group is 50% ionised
o pH is below pKa – group will have H attached
o pH is above pKa – group will lose H+

, PRIMARY AND SECONDARY STRUCTURE


PRIMARY - number, sequence and order of amino acids in a peptide chain
 Determined by gene which codes for protein, gene transcribed to produce mRNA, then translated on the ribosome
 Unique properties of proteins are determined by the order of amino acids and their R groups

Amino acid polymers
 Backbone – amino acid chain
 Residue – an amino acid in a polypeptide chain
 Side chains – R groups
 A polypeptide chain has direction as the amino acids have different ends

Formation of peptide bonds (amide bonds)
 Formed at ribosome
 The peptide bond resonates between two forms – makes the bond quite rigid
 C-N shows double bond characteristics, limited rotation
 O and H positioned at opposite sides of the bond – trans position – maintains maximum distance between them
which is sterically most advantageous

SECONDARY- local spatial arrangements of amino acids in the peptide chain
 Stabilised by H-bonds arising between O in peptide bond and N in another peptide bond
 α- helix
o Formed by backbone of the chain, set number of residues per term
o H-bonds between the N-H and C=O groups (intrachain H-bonds) of the main chain
stabilise the helix
o Side-chains stick out form the helical structure
o Each C=O oxygen is H-bonded to N – H of amino acid 4 residues ahead: 1-5, 3-7, 2-6
o H-bonds nearly parallel to helix axis – gives some elasticity to the helix
 -pleated sheet
o Stabilised by H-bonding between adjacent strands; between 2 part of the same chain
(intrachain) or between different amino acid chains (interchain)
o Side-chain lie above/below plane of sheet
o Fully extended polypeptide chain
o No elasticity
o Tetrahedral angles separating bonds of the carbon give a pleated appearance
o Loops and turns allow for the change in direction of the chains

TERTIARY AND QUATERNARY STRUCTURE


TERTIARY - organisation of primary and secondary structures into the 3D protein shape
 Interior of soluble proteins is hydrophobic (e.g. Leu, Val, Met)
 Exterior of soluble proteins is mostly hydrophilic (e.g. Arg, Lys, Glu)
o Most proteins have small exposed hydrophobic regions
 Amino acids are brought together in the folded protein to assemble the
active site of an enzyme
o Each of the amino acid residue interacts with the substrate to
position it correctly and catalyse the conversion of substrate to
product

QUATERNARY - arrangement of different subunits in space
 Multi-enzyme complexes – mitochondrial ATPase
 Motility proteins – myosin
 The interfaces between subunits contain closely packed non-polar side chains, hydrogen bonds and sometimes
disulphide bonds

Forces that stabilise tertiary and quaternary structure
 Packing of helices, sheets and different subunits are stabilised by sidechain interactions
 Interactions vary in strength