Relationship between Gene Mutations, Amino Acid Side Chains, and Protein Structure

1. Chapter 13 & 14 Essentials of Genetics Relationship between Gene Mutations, Amino Acid Side Chains, and Protein Structure

2. 13.8: Chemical Nature of R-Groups Each Side Chain has a characteristic chemical behavior. This behavior will determine the Secondary and Tertiary structure of a folded protein.

3. Predictable Behavior of Side Chains • Hydrophobic – R-groups will force the protein to fold and allow this side chain to be away from water. • Hydrophilic – R-groups want to be toward water. • Acids – R-groups will form ionic bonds with R-groups that are Bases. • The 3-D structure is a PRODUCT of the primary order of amino acids.

4. Protein Structure, a Reminder… • Primary – straight chain of amino acids held together by peptide bonds. • Secondary – alpha helix or beta-pleated sheet held together by hydrogen bonds. • Tertiary – globular structure; 3-dimensional shape determined by side chain chemistry of individual amino acids. • Quarternary – more than one tertiary structures that fit together in a complimentary way.

5. How Does a Polypeptide Become a Protein? • Folding occurs in the watery cytosol • HydroPHOBIC amino acids want to be • Near other hydrophobic amino acids • Away from the watery cytosol/in the interior of the folded structure. • HydroPHILIC amino acids are located along the surface/outer edge • Disulfide bonds form between cysteine molecules. • Acids and bases form ionic bonds.

6. The Role of Chaperones • Chaperones are proteins that assist in the folding of other proteins. • Mediate the process of folding by preventing the formation of incorrect patterns. • They do not become a part of the final product although they do bind to the polypeptide as it is folding. • If the correct structure is NOT made UBIQUITINS tag them for destruction by proteasomes.

7. Impact of Mis-folding • Mis-folded proteins can be nonfunctional • Sickle Cell Anemia • EB • OI • Cystic fibrosis • Mis-folded proteins can accumulate and cause cell destruction. • Prion Diseases • Huntington Disease • Alzheimer Disease • Parkinson Disease

8. 13.9: Proteins Have Diverse Roles • Proteins are the essence of cellular function. • Most abundant organic macromolecule in cells. • Structural/Fibrous proteins like collagen and keratin • Contractile proteins like actin and myosin • Functional/Globular proteins like hemoglobin, myoglobin, and immunoglobulins • Largest functional group - Enzymes – biological catalysts that require a specifically shaped ACTIVE SITE for normal function.

9. 14.1 Mutations Are Classified in Various Ways • Mutation is any base pair change. • Can involve a single base pair substitution, deletion or insertion of one or more bases, or major alterations in chromosome structure. • How they occur: Spontaneous or Induced? • Where have they occurred/location? • Somatic • Germline • Autosomal • X-linked

10. 14.1 Spontaneous or Induced • Spontaneous mutations appear to have no known cause. • No known agents are associated with this occurrence. • Assumed to be accidental. • Induced mutations are due to an extraneous factor that may be natural or artificial. • Examples include radiation and both natural and man-made chemicals. • We call these MUTAGENS

11. 14.1 Location • Somatic occur in any cell except gametes • Mutations DO NOT pass on to offspring • Germline occur in gametes • Mutations DO pass on to offspring • Autosomal occur on autosomes • X-linked occur on X chromosomes • Express differently in males and females due to presence of 1 or 2 X chromosomes. • Description of mutation can be combination of above terms: • Autosomal somatic • Autosomal germline • X-linked somatic • X-linked germline

12. Classification Based on Type of Molecular Change If the triplet code does not

13. Point Mutation • Change in ONE nucleotide of a triplet • Occurs in protein-coding (exon) portion • Creates NEW triplet code • Same amino acid = silent mutation (degeneracy) • Different amino acid = missense mutation • Same side chain group has less impact than different side chain group. • Results in STOP codon = nonsense mutation • Frameshift Mutation • Alters reading frame, changes every amino acid following insertion or deletion.

14. What is their Phenotype effect? • Loss-of-function • Gain-of-function • Morphological • Nutritional • Behavioral • Lethal • Conditional

15. Loss-of-function – reduces or eliminates function of gene. • Null mutation – complete loss of function. • Gain-of-function – enhanced or new function. • Morphological – visible alterations of phenotype. • Nutritional – loss of ability to synthesize an amino acid or vitamin. • Behavioral – difficult to analyze; defect that changes mating behaviors, etc. • Lethal – interrupts process essential to survival. • Conditional – expression depends on environment.