How can proteins become functional
- be folded to active 3D structure
- must bind to cofactors
- must be modified by protein kinases
- join other subunits
Describe molten globule state
-intermediate state in-between protein folding which happens in seconds after leaving ribosome and has alpha helixes and beta sheets
Disadvantage of misfolded proteins
- waste of energy to cell
- hydrophobic regions aggregate causing disease
2 mechanisms by which cells defend against misfolded proteins
1 proteasomes
2 chaperones
What are chaperones
-proteins which help other nascent proteins fold properly
What system are chaperones part of and describe briefly
- quality control system
- protein control system : mechanism allows cells to monitor protein synthesis and ensure they are in a stable and inert state
Functions of chaperones
- rescue misfolded proteins back to normal nascent state
- prevent protein degradation : normally folded not ubiquitinated
- prevent aggregation
- prevent prion formation
- assist in translocating proteins
- assist in protein folding
What is a client protein
-protein helped to fold properly by chaperones
How do chaperones aid in protein folding
-they bind to aggregation prone hydrophobic region and use ATP hydrolysis to perform mechanical work on protein and ensure correct folding
How are chaperones made, example and why and their synonym
- made during severe stressful conditions undergone by a cell
- eg extreme heat denatures proteins and chaperones are needed to deal with denatured proteins
- heat shock proteins
Types of chaperones and examples
1 heat shock HSP 10 - Gro ES HSP 60 - Gro EL HSP 70 - DNA K HSP 40 - DNA J
2 lectin chaperones
- calnexin
- calreticulin
3 Glucose Regulated Proteins GRP-58
4 Protein disulfide isomerase
Function lectin chaperones
-function in immune system by antigen processing and presentation in MHC class 1 molecule
Function of GRP-59
-assist in glycoprotein folding
Classification of proteins based on function and describe and examples
1 foldases - transform misfolded back up nascent state
- assist in folding
- ATP dependent
- HSP 60
2 holdases- prevent damage to protein by providing favorable conditions
- do not fold or correct misfolded proteins
- HSP 70
3 disaggregases - prevent aggregation
- rescue aggregates proteins
- prevent prion formation
- HSP 104
List the 3 ways in which proteins can processed
1 on pathway folding
2 off pathway folding
3 proteasome system
Describe on pathway folding
- linear sequence goes into intermediate molten globule state
- under normal conditions globule transformed into final state
Describe off pathway folding
- sometimes intermediate deviates from pathway leading to misfolding
- chaperones catalyze protein to return to normal pathway
- protein gets correctly folded
Describe proteasome system
- sometimes chaperones fail you catalyse misfolded protein back to pathway
- protein ubiquitinated and degraded
When do chaperones assist in folding and give examples
- co translational : HSP 70
- post translational: HSP 60
Function of HSP 70 and its domains
-mediates folding of newly ( co ) synthesized proteins
1 atp binding domain - n terminal
2 substrate binding domain -inside cavity
3 c terminal - provides cavity for substrate
ATP bound to HSP 70 forms !?
-open complex confirmation
Describe how HSP 70 mediates folding
- HSP 40 recruits substrate to HSP 70 where It binds to cavity at aggregation prone hydrophobic region
- HSP 40 and atp bringing to HSP 70 causes hydrolysis and lid closed forming closed conformation
- protein folding commences inside cavity when lid closed
- 40 leaves and nucleotide exchange factors convert adp to atp
- open complex formed at folded protein leaves
Function of HSP 40
- recruits substrate to HSP 70
- regulates atp activity
Describe what proteins are acted upon by HSP 60 and its shape
-completely synthesized proteins
/barrel like
