IN THE NAME OF GOD

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Molecular chaperones

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DEFNITION heat shock proteins Role of Molecular chaperones Two classes of molecular chaperones have been well studied Hsp70 & hsp40 DnaK & DnaJ Chaperonins two enzymes (PDI) & (PPI) Misfold Human Genetic Disorders 2

SOME PROTEINS UNDERGO ASSISTED FOLDINGNot all proteins fold spontaneously as they are synthesized in the cell. Folding for many proteins is facilitated by the action of specialized proteins. Molecular chaperones are proteins that interact with partially folded polypeptides or improperly folded, facilitating correct folding pathways or providing microenvironments in which folding can occur.

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ChaperoneChaperone noun [ C ]

also chaperon UK /ˈʃæp.ə.rəʊn/ US /ˈʃæp.ɚ.oʊn/

(especially in the past) an older person, especially a

woman, who stays with and takes care of a younger woman

a female nurse ; an older person ; an adult

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HEAT SHOCK PROTEINS The Hsp70 family of proteins generally have a molecular weight near 70,000 and are more abundant in cells stressed by elevated temperatures (hence, heat shock proteins of Mr 70,000, or Hsp70)

Classified with molecular weight

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R0LE OF MOLECULAR CHAPERONES proteins also block the folding of certain proteins that must remain unfolded until they have been translocated across a membranefacilitate the quaternary assembly of oligomeric proteins“protect”both proteins subject to denaturation by heat and new peptide molecules being synthesized (and not yet folded)facilitating correct folding pathways or providing microenvironments in which folding can occurTransduction of protein from synthesized to target organsContribute folding of signaling transduction proteins (esteroids hormonse receptor &tyrosine kinas receptor by HSP90)Contribute degrade of misfoldings proteins05/01/2023 A.RJN 6

TWO CLASSES OF MOLECULAR CHAPERONES HAVE BEEN WELL STUDIED

Both are found in organisms ranging from bacteria to humans

The first class, Hsp70The second class, chaperonins

BIP proteins in endoplasmic reticulum are homolog of HSP70. Hsp70 proteins bind to regions of unfolded polypeptides that are rich in hydrophobic residues,05/01/2023 A.RJN 7

HSP70 &HSP40

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The pathway by which Hsp70-class chaperones bind and release polypeptides is illustrated for the eukaryotic chaperones Hsp70 and Hsp40.

The chaperones do not actively promote the folding of the substrate protein, but instead prevent aggregation of unfolded peptides.

The unfolded or partly folded proteins bind first to the open, ATP-bound form of Hsp70 (PDB ID 2QXL).Hsp40 then interacts with this complex and triggers ATP hydrolysis that produces the closed form of the complex (derived from PDB IDs 2KHO and 1DKZ), where the domains colored orange and yellow come together like the two parts of a jaw, trapping parts of the unfolded protein inside.

Dissociation of ADP and recycling of the Hsp70 requires interaction with another protein, nucleotide-exchange factor (NEF).

For a population of polypeptide molecules, some fraction of the molecules released after the transient binding of partially folded proteins by Hsp70 will take up the native conformation.

The remainder are rebound by Hsp70 or diverted to the chaperonin system (Hsp60; see Fig. 4–31).

In bacteria, the Hsp70 and Hsp40 chaperones are called DnaK and DnaJ, respectively.DnaK and DnaJ were first identified as proteins required for in vitro replication of certain viral DNA molecules (hence the “Dna” designation).

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DnaK & DnaJ

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The cyclic pathway by which chaperones bind and release polypeptides is illustrated for the E. coli chaperone proteins DnaK and DnaJ, homologs of the eukaryotic chaperones Hsp70 and Hsp40. The chaperones do not actively promote the folding of the substrate protein, but instead prevent aggregation of unfolded peptides. For a population of polypeptides, some fraction of the polypeptides released at the end of the cycle are in the native conformation. The remainder are rebound by DnaK or are diverted to the chaperonin system In bacteria, a protein called GrpE interacts transiently with DnaK late in the cycle(step 3 ), promoting dissociation of ADP and possibly DnaJ. No eukaryotic analog of GrpE is known.

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CHAPERONINSThe chaperonins first became known when they were found to be necessary for the growth of certain bacterial viruses (hence the designation “Gro”)

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(a) A proposed pathway for the action of the E. coli chaperonins GroEL (a member of the Hsp60 protein family) and GroES. The analogous chaperonin system in eukaryotes is called Hsp60

Each GroEL complex consists of two large pockets formed by two heptameric rings (eachsubunit Mr 57,000).

GroES, also a heptamer (subunits Mr 10,000), blocks one of the GroEL pockets.

(b) Surface and cut-away images

of the GroEL/GroES complex (PDB ID 1AON). The cut-away (right) illustrates the large interior space within which other proteins are bound.

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TWO ENZYMES Finally, the folding pathways of some proteins require two enzymes that catalyze isomerization reactions. Protein disulfide isomerase (PDI) is a widely distributed enzyme that catalyzes the interchange, or shuffling, of disulfide bonds until the bonds of the native conformation are formed. Among its functions, PDI catalyzes the elimination of folding intermediates with inappropriate disulfide cross-links.

Peptide prolyl cis trans isomerase (PPI) catalyzes the interconversion of the cis and trans isomers of Pro residue peptide bonds (Fig. 4–8), which can be a slow step in the folding of proteins that contain some Pro peptide bonds in the cis conformation. 05/01/2023 A.RJN 17

MISFOLDA soluble protein that is normally secreted from the cell is secreted in a misfolded state and converted into an insoluble extracellular amyloid fiber. The diseases are collectively referred to as amyloidoses

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HUMAN GENETIC DISORDERS•Many conditions, including• type 2 diabetes,•Alzheimer disease, •Huntington disease, •Parkinson disease, •are associated with a misfolding mechanism

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REFERENCESLehninger fourth editionLehninger sixth editionThe chaperonopathiese alberto i.l macario

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