High Order Protein Structures

7/28/2019 High Order Protein Structures

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Higher Order Protein Structures

Winston S. Abena, RMT, MD, DPASMAPCollege of Medicine and Surgery

Cagayan State University


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Molecular forces involved in protein

structure

Protein folding

Structure and biosynthesis of collagen


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Protein Native State

and Denaturation

A protein folded into its tertiary

structure under optimal conditions is

said to be in its native state, which

corresponds to its most thermo-

dynamically favorable arrangementof atoms. Proteins can be denatured

(loss of their secondary and higher

structures) by changes in temperature,

pH, ionic strength, urea or detergents


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Proposed Folding Pathway

Accessoryproteins?


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O-H = 460C-H = 410C-C = 350

Bond kJ/m

Compare:


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Non-covalent Molecular Forces

in Protein Structure and Folding

Hydrophobic interactions: interactions between

hydrophobic amino acids is likely the largest

noncovalent force responsible for most protein

folding. Recall that water will tend to form a

solvation shell around free hydrophobic compounds,

which in thermodynamic terms, is a decrease in

entropy (and thus not favored). This drivesformation of hydrophobic regions of protein chains

to come together, the water shell is disrupted and

entropy increases.


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Non-covalent Forces (cont)

For hydrophobic interactions, calculations have

shown that 1/3 loss of water of solvations occurs

with formation of secondary structure; an additional

1/3 water of solvation is lost in the formation of

tertiary structure. This is a large source of the energythat drives protein folding.

Hydrogen Bonds - these have been discussed for

helix and sheet formation. Distance between thedonor and acceptor atoms are the most important

determinants for bond formation, 2.7-3.1 angstroms

are optimal (covalent bond is 1.0-1.6 angstroms)


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Electrostatic, or charge-charge interactions.

Predominantly found on the exterior

surfaces of proteins, interacting with the

water solvent. The strength of the ionic

forces are largely dampened by the high

dielectric constant of the surrounding water,

such that proximity to other charged groupsis likely the strongest attractive force for

charge-charge interactions


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Van der Waals interactions: Occur when molecules

or atoms which do not have covalent bonds between

them come so close together that their outer electron

orbitals begin to overlap. This can lead to changes in

the overall distribution of the electronic charges to

create a weak attractive force. Contact distance

ranges from 2.8 to 4.1 angstroms, so forces areweak. However, in a folded protein, thousands of

individual interactions occur, thus providing a

significant cumulative stabilizing force.


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Accessory Proteins for Folding

In a test tube,protein renaturation of an

unfolded protein can take minutes, days or

never occur. Protein folding in the cell

occurs during protein translation (synthesis)

and generally takes only a few minutes for

formation of the native conformation. This

is primarily due to the inherent properties ofthe protein, and is assisted by cellular

accessory proteins, examples of which

include:


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Accessory Proteins (cont)

Protein disulfide isomerase - catalyzes

formation of disulfide bonds

Peptidyl Prolyl Cis-Trans Isomerases - this

class of enzymes, also called rotamases,

facilitates the conversion of Pro residues tocis-conformations (originally made in a

trans conformation)


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Accessory Proteins (cont)

Chaperones - a large group of proteins, alsotermed heat shock proteins and chaperonins,

their precise regulation and mechanisms of

action remain largely undefined. During the

folding process, they function to prevent

unfavorable protein interactions with other

potentially complementary surfaces (like

other proteins, carbohydrates, lipids, nucleicacids, etc.) Many of these proteins are

ATPases (use hydrolysis of ATP as an

energy source).


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Fibrous Proteins - Examples and

Characteristics

Highly elongated proteins whose secondary

structures are the dominant structural motif

Found in skin, muscle, tendon and bone and haveconnective, protective and/or supportive

functions

EXAMPLES: keratins (hair, nails, horn,feathers)elastin (tendons); spider silk fibroin; collagens


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COLLAGEN: Properties

Most abundant protein in mammals example of a fibrous protein (in general,

these protein have repetitive secondary

structures, are poorly soluble, and cannot be

crystallized; other fibrous proteins include

elastin in tendons & keratins in hair and

nails)

collagen composed of approximately 33%

glycine, 21%proline orhydroxyproline, and

11% alanine


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COLLAGEN: Properties (cont)

Tropocollagen (the precursor form) is

composed of three polypeptide chains ofabout 1000 amino acids each, wrapped in a

triple helix, rope-like coil

Every third residue in each polypeptide inthis triple helix is a glycine. The glycines

from each strand interact with each other in

the central, shared interior of the helix Proline frequently follows glycine, and the

third residue can be any otheramino acid

(X) found in collagen; a Gly-Pro-X motif


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COLLAGEN: Properties (cont)

Extensive post-translational modification of

prolines and lysines occurs

Cross-linked fibrils of collagen form after

secretion and processing of tropocollagen

Defects in enzymes involved in the collagen

biosynthetic pathway are responsible for

many diseases.


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Synthesis of Hydroxyproline and

Hydroxylysine residues


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Formation of collagen

cross-links: Mediated bylysine modifications and

subsequent lysine-allysine

or allysine-allysine covalent

bond formation


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Post-translational

processing of

collagen


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Marfan syndrome is caused by mutations in the fibrillin gene; Fibrillin is

a large fibrous protein component of extraocular microfibrils, frequently

associated with elastin


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High Order Protein Structures