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why study proteins
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- 1what happens once a protein leaves the ribosomeOnce a protein leaves the ribosome can adopt the fold that is required for its function
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- Many require there to be a tertiary structure - 2what is the effect of mis-folding proteins- Proteins may misfold- this can lead to aggregation further to this aggregation can lead to the formation of amyloid fibrils
- Proteins may be degraded after they have carried out their function or if they are detected as misfolded - 3describe the motivation to understand protein mis-folding in terms of cystic fibrosis- most common inheritable condition in Europe
- 1/2000 people are born with C.F.
- The protein that is at the centre of this condition is called the cystic fibrosis transmembrane conductance regulator (CFTR)—> this protein is formed of 1480 residues
- Sits in the membrane with binding sites in the cytosol
- The role of the protein is to pump chloride ions out of the cells
- In 70% of C.F. Cases the condition is caused by a single amino acid deletion of phenylalanine 508—> although there is 1000 different known mutations - 4what is the effect of a point mutation in phenylalanine 508 in the cystic fibrosis trnasmembrane conductance regulator (CTFR)Understanding of this is due to cryoEM
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- The phenylalanine 508 sits in a nucleotide binding domain
- Sitting at an interface of this domain with the transmembrane domain 2- extending into the membrane
- This residue is not required functionally for the chloride export, or binding of the nucleotide or ATP but plays a structural role
- Hence the removal of this residue means that the protein doesn’t fold quickly enough within the cell and therefore is targeted for degradation
- Based on these structural insights there is new treatments that are emerging - 5describe the motivation to understand protein mis-folding in terms of cancerProteins regulate the expression of genes
- One of the most prevalent transcriptional regulators is a protein called P53
- This is a tetramer is protein that wraps around the DNA and regulated the cell cycle and activates repair processes
- Can induce cell death
- In over 50% of all human cancers there is a mutation on the p53 can leads to irregular functioning
- Clear understanding of this protein and how mutations effects the function could lead to there restorative or inhibitory methods
- Some of the mutations that affect p53 functioning do not simply affect it ability to bind to DNA, but how the protein is folded—> understanding could = treatment - 6summarise the work of Christian De DuveTaking a peptide containing 10 amino acids, with the aim of producing one molecule of every variant there is 1.02x 10^13 different sequences- the total mass of this would be 2.28x10^-8grams—> this is very little
Comparing this to 100 amino acid there is 10^130 different sequence combinations- making one molecule of these would not be possible as there is not enough atoms in the known universe. The mass of such would equate to 2.22x10^110 (which is 10^54 times the mass of the universe
- Massive complexity - 7describe the relationship between the genome, trascriptome and proteomegenome- 19965 human protein encoding genes
transcriptome- 83986 human protein encoding transcripts
proteome -unknown (PTMs)
current estimations suggests that there is between 600000 and 6 million - 8describe how all the proteins sequences that are known could not have be explored by evolutionthere are 10^130 possible sequences
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- 20 amino acids is not necessary for a functional protein
- Likely that the evolution of proteins started with only a handful of amino acids
- Despite the complexity there are only a few thousand different folds despite there being a huge sequence diversity
- Most larger proteins are made of much smaller building blocks of <100 amino acids (large proteins have evolved from much smaller ones- how functional proteins may have evolved through evolution)
- The amino acids that are found in extraterrestrial materials are the first amino for the origins of life —> not all were present at the start - 9what does the reduced repertoire of the chorismate mutate enzymeWT= 9/20 amino acids
reduced repetoire variant =9
only 38% of the residues couldn't be mutated
70% similarity between the 2
bacteria with the reduced repertoire gene = survive
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Convincing experiment showing that proteomics doesn’t have to be considered as complex as it initially seems - 10what is the most common fold found in proteinig-like B sheet
found in 1.5% of all proteins - 11name 2 proteins that have the same structure (similar) that have unrelated functionsHuman fibronectin and bacterial invasin
- 12what is the function of the human fibronectin- Human fibronectin is one of the most abundant within the body- is required for cells to bind to tissues
- 13what is the cellular function of the bacterial protein invasinsits on the bacterial membrane allowing it to invade human tissues
- 14what are the similarities between the human fibronectin and the bacterial invasincontain the same fold/ topology, despite the protein having no functional similarity
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- Sequence is not particularly related either - shows only a 11% sequence identity (10-15% identity is to be expected during the comparison of any two sequence of this length purely by chance)
- Highlights that the complexity of proteins is not as high as we like to assume due to maths - 15example of conservation of the function of a proteins despite there being sequence and fold diversityChymotrypsin and subtilisin are two proteins that have the same cellular function—>Proteases
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re both mixed helical beta sheets but the precise topology differed dramatically between the two
- Catalytic triad that is conserved between the two- serine, histidine, and aspartate Which can be found orientated the same between these 2 - 16what is the catalytic triadserine, histidine, and aspartate
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A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. - 17what is the proportion of proteins that are natively unfolded/do not have a tertiary structure1/3
- Either entirely unfolded or have sections of the sequence that are unfolded
- NMR is a great technique to study this
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- Protein structure and function Karteikarten am why study proteins , erstellt von Samantha bruce am 05/12/2019.
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