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BIOL 4030 Lecture Notes - Coiled Coil, Alpha Helix, Structural Genomics

Course Code
BIOL 4030
Logan Donaldson

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Proteomics –
The Science of Proteomics
Proteomics is the study of protein structure and function at a large scale
The name is derived from genomics (the study of genomes)
Started in 1997
SNPS – differences are extrememly old and can be used to look at migration patterns. Genomics looks at whats different among
proteome changes between cells and tissues unlike DNA so studying it gets even more difficult
Protein called β€œNotch”, which makes a B-line for nucleus
Mass spectrometry is the main method of study to examine proteins
a recent study showed that amount of mRNA in a cell does not reflect the amount of protein being made interestingly
Post-translational modifications
simple phosphorylation: very good way of modifying protein activity
~2% of our proteome encodes kinases (~500 proteins)
serine, threonine and tyrosine are commonly phosphorylated
ophosphotyrosine: SH2 domain
extremely powerful signal because it calls upon other protein to cause chain reactions
ST1571 aka GLEEVEC: drug that’s a hybrid protein. Works on domains of protein Bcr-Abl which is a tyrosine kinase
oExpensive drug that REALLY works for cancers like leukemia (covered in Canada)
Platforms for Proteomics and Functional Genomics
figure shows how complex proteomics is
topics prof will cover:
omass spectrometry
oGFP + FRET fluorescence
oProtein Arrays
oChemical Arrays
oAntibody Arrays
HERCEPTIN: drug that works on receptor kinases
Botulism toxin payload + Antibody
Array Based Proteomics
FRET (fluorescence resonance energy transfer): two fluorescently tagged molecules/proteins come together, detect
by shining light on one molecule which emits a certain wavelenth which is absorbed by the protein nearby which then
emits a different wavelength
How to tag a protein: GO after an animo acid that has a specific chemical reactivity. A popular method is looking at
cysteine which is rare on the surface on a protein.
oThiol groups: make disulfide bonds
oAmino groups (NH3+):
Structural Proteomics
X-ray crystollagraphy and NMR spectroscopy are the two main methods
oRIKEN is a company in Japan that has a factory that just find structure of proteins
Clinical Proteomics
NMR of urine can have a thousand peaks but each person’s pattern is different? Each peak ofcourse corresponds to a
certain protein or compound but they’re only interested in the pattern
Even if your sick, knowing your protein complement is important ex. Your doctor can change your prescription or
therapy based on it

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Lecture 2 – September 20, 2010
Levels of Protein Structure
Primary: just the sequence of the protein
Secondary: alpha helices (right-handed) and beta strands
Teritary: global fold of protein
Quatenary: bunch of proteins together
Amino Acids
generally two classes: hydrophobic, hydrophilic
alpha carbon contains R-group
oR = H: glycerin
oR = methyl: alanine etc
Substition Chart shows what can be tolerated
Its more difficult to make a substitution for an interior amino acid than for an exterior. In general assume that when
you replace an a.a. it’ll be replaced by an a.a within its group eg. Aliphatic, hyrdrophobic for hydrophobic
To make or break peptide bond just add or substract water
oNot only are the planars flat but they have diploes as well
Torsion Angles: depending on which side of the Calpha you’re at.
oProtein can be expressed simply as a table of phi and psy
Ramachandran Map
what are the allowable angles in a protein? He discovered them…certain angles aren’t allowed, in fact most aren’t only
certain angles shown in red dots, red brown is more common and brown is slightly common? Grey is forbidden
Prof’s Work
triangles are glyceins and assumes a lot more conformation so it can go almost anywhere on the map
Side Chain Torsion Angles
again you don’t see every angle, steric repulsion (where atoms bump into each other). 60, 180 and 300 degrees are the
most favourable ….especially for the big buly amino acids like phe follow those angles
ξ€β€œclick” the
Torsion angle dynamics: much more efficient…not sure why
Weak Forces
help protein fold and are broken easily
If you take a sequnces of a protein and let it fold, its important in the study of diseases like Mad Cow. Some times you have a
good form of a protein and sometimes it forms a bad form which serves as a nucleus to turn the good proteins to bad ones.
when proteins change structure they tend to stick together in odered fashion (oligermize) likein alzheimers. Aggregates
of protein can kill proteins around them.
proteins are always vibrating and are not static as shown in many pictures
main thing in proteins: slow motions in terms of millisecond to microsecond time scale, movements include loops
moving back and forth, protein looks like its breathing
protein folding can happen in less than a second, (tenths of a second being the max)
The Alpha Helix
hydrogen bonds play big role, they help stabilize the structure
I don’t get the deal with i and i+4 and something about affecting the width of the protein
Beta Strands
The Beta Turn
two H-bonds are formed in this turn
only come in certain shapes and show a.a preference for positions 2 and 3
Lecture 3 – September 22, 2010

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The Beta Turn
H’s have to be 1.8 to 2.0 Angstroms to bond so adjacent H’s wont bond as they’re too far
Amino Acid Preference for Secondary Structures
Computer servers and algorihms help predict alpha helices and beta strands in a given protein sequence
Certain amino acids have a preference to be in a certain structure (add chart from slides)
oSome prefer alpha helices some prefer beta strands
o1.0 is no preference a portal to software that allow you to predict protein structure
Richardson Diagram
shows two pics of 4 beta strand proteins and three hairpins
only shows protein backbone and doesn’t include protein side-chains
Topology Cartoons
compares a given protein to all other proteins in the database
triangle is a beta strand etc.
instead of having to search through database you can search with the motif of the simple shapes
Prof worked on gpU (β€œneck” protein between capsid and tail).
The sequence of this strange protein is so unique it shows no similarity to any other species. It has no homologue!
ogpU is a hexomer and acts as a monomer and makes a polymer of six units
a)just shows accumulation of data…the more trials the more they should fit (if it doesn’t fit its because of
protein motion skewing data slightly…it sampling many conformations)
b)shows one beta strand network (b1 and b2 are parellel to each other, a couple helices). When you search
the motif in the database you get the shapes shown under c
c)Nature likes the general shape of the protein structure?
Virus have gpV for body or tunnel of the virus (tail protein), gpH determines its length (tells gpV when to stop)
If you look at enough structure you can get different rules…a protein folding language developing
Helix Packing
a helix presents certain aa at certain places (he drew a diagram)
20’ and 50’ for packing tubes
just appreciate the fact that secondary structures interact with other secondary structure in different ways
Helices have this β€œnotching log” characteristic (like a log cabin)
odone by having two glyceins
Coiled Coil (red and blue pic…rest were skipped)
coiled coil have some flexibility to them that are actually stable structures
otwo forms: antiparallel and parallel
Binary Coiled Coils
going around a helix there are 7 positions you have to consider and there are certain preferences of amino acid for each
If you have 2 helices close together you have hydrophobic reaction at the interface and that forms the β€œnothch”
You have ionic and Van der waals interactions to make a very stable structure
You can even form a β€œhelix of helices”
Transcription factors COied Coil Complex
coiled complex are found in nature
fos/jun makes the particular motif β€œleucine zipper” that interacts with the major grooves in DNA (interactions
composed mostly of ionic forces)
three different SNARE PROTEINS
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