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Maivel H. Ghattas, M.D. Prof. of Medical Biochemistry

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To identify the primary, secondary, tertiary & quaternary structures of proteins. 2) To list the features of a peptide bond. 3) To compare the methods for determining amino acid sequence of a protein. 4) To describe the concept of domain structures in proteins. 5) To describe diseases due to protein misfolding

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Primary structure is the sequence of amino acids in protein.

Abnormal amino acid sequence of proteins can lead to disease.

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Uncharged (do not give up or accept protons). However, they can form hydrogen bonds.

peptide bond  (Fig. 2.2B) a) has "partial double bond“ characteristics – no free rotation around a peptide bond; rigid and planar b) rotation on either side of  a -carbon can occur (with the exception of pro). Thus, variation in three dimensional structure can occur. c) peptide bond almost always  trans d) groups in amide bond – uncharged (do not give up or accept protons). However, they can form hydrogen bonds (important)

Has “partial double bond”  No free rotation around a peptide bond; rigid and planar.

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polypeptides are named with the first a.a being the one with a free   -amino group. "-yl" is used as suffix, except for last (carboxyl) aa. Amino acid sequence with free amino terminus is written to the left, free carboxyl terminus to the right

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Rotation on either side of   -carbon can occur (with the exception of pro).

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Spiral structure, tightly packed, coiled.  Side chains (R-groups) point outward from spiral. Hydrogen bonds stabilize  the  helix. C=O group of one a.a. forms H bond with NH group of  4th  a.a.

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Combination of many weak H bonds cause very stable structure.  All NH and C=O groups are in H bonds, except those in the first and last a.a. in the helix.  3.6 a.a. per 1 turn of the   -helix. results in more compact structure.

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proline breaks   -helix because of imino structure. Puts in a kink. Highly charged aa's (asp,glu,his, lys, arg) – many ionic bonds disrupt helix. Many aa's with bulky side chains (trp) or branched side chains (val, ile) disrupt the helix.

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H bonds perpendicular to polypeptide backbone Antiparallel or Parallel. Sheet is "pleated" in structure.

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Interchain H bonds: between two different polypeptide chains. Intrachain H bonds: between aa's in the same polypeptide chain

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 -bend,  (    -turn; reverse turns)

1) reverses direction of polypeptide chain - helps form compact, globular shape. 2) often found on surface 3) often have charged aa's, gly (small, fits), and pro (causes "kink")

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Domains: "fundamental functional and 3D structural. A combination of motifs forms a domain. A domain is usually globular. Each domain folds independently of other domains.

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Interactions that stabilize tertiary structure 1)  Disulfide bonds:  (two cysteine)  (-SH) oxidize and form a disulfide bond. Can be located on the same polypeptide chain (intrachain) or on different polypeptide chains (interchain). Strong covalent bond that keeps protein folded in a 3D (tertiary) structure)

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2)  hydrophobic interactions  : nonpolar groups (generally in interior) associate with themselves and stabilize tertiary Structure. 3)  Hydrogen bonds:  polar uncharged aa's, mostly (C=O, NH)

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4)  Ionic interactions  (salt bridges): polar charged amino acids – asp, glu, lys, arg (COO-, NH3+)

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Multiple subunits interacting together (2 = dimer; 3 = trimer;4 = tetramer, etc.)  Interactions stabilized by noncovalent bonds (hydrophobic interactions, H bonds, ionic bonds)  Subunits may act independently or cooperatively

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side chain interactions of nearby amino acids assist in the rapid folding by maximizing favorable interactions (attractions) but minimizing unfavorable interactions (repulsion). Occurs in a local, orderly, stepwise fashion

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Prevent improper or early folding when protein synthesis is occurring. 1) many of these are "heat shock" proteins induced by stress. Help refold some proteins 3) if large proteins are denatured, they will often not properly fold even with chaperones present.

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A) Unfolding and disorganization of protein structure. B) Peptide bonds NOT broken C) Heat, organic solvents, detergents, physical agitation, heavy metals.

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D) urea, guanidine hydrochloride, Pb, Hg. E) Once denatured proteins rarely renature properly. Exceptions  (ribonuclease).

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Abnormal proteolytic cleavage can generate protein fragments that can form  b -pleated sheets and then associate to form long fibrous aggregates called amyloids. Alzheimer’s Disease  amyloid plaques in brain .

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Transmissible disease, but the infectious agent is NOT a nucleic acid (DNA, RNA) as is true in virally transmitted diseases. The agent is a  misfolded protein  (PrP)!!

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Enzymes       Enzymes are mainly proteins Hormones      peptides (glucagon) or protein (insulin) Structural proteins      Collagen and elastin

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Defense mechanisms       Immunoglobulins (Ab)       Keratin of the skin Transport  Carrier of molecules Hb , Plasma lipoproteins, Glucose        transporters

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Cell membranes       contain proteins Storage      Ferritin the storage form of iron

Protein Structure

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