2.8 Protein Structure 4 - Sequence, structure and function

Introduction to Protein Structure

Topic: Protein Structure

This course delves into the intricate relationship between the amino acid sequences of proteins and their three-dimensional structures, ultimately determining their biological functions. Understanding this relationship is critical for advances in fields like molecular biology, genetics, and biochemistry.

Homology in Proteins

Definition of Homology:

Homology refers to the similarities observed in sequence and/or structure between proteins or genes, suggesting a common evolutionary origin.

Key Points:

  • Homologous proteins share similarities due to descent from a common ancestor.

  • Example: If two proteins have 97 identical amino acids out of 211 total, they have a sequence identity of 46% (this does not imply they are 46% homologous).

Structural Homology:

Structural similarities may extend beyond sequence to two proteins having similar structural arrangements.

  • Protein 1: 200 amino acids, exhibits a barrel structure.

  • Protein 2: 211 amino acids, also adopts a barrel structure.

Genetic Diseases and Mutations

Cause of Genetic Disease:

Genetic diseases often arise from mutations, which are changes that occur in the DNA sequence affecting a single amino acid residue or multiple residues in proteins.

Examples:

  • Sickle Cell Anemia: A point mutation where the amino acid glutamic acid (glu6) is replaced by valine (val6) in hemoglobin, leading to abnormal red blood cell shapes and function, causing severe health issues.

  • Cystic Fibrosis: Resulting from the deletion of a three-base pair segment in the CFTR gene, this removal of phenylalanine leads to issues in chloride ion transport, resulting in thick mucus production and organ dysfunction.

  • Hereditary Nature: Many genetic defects can affect individuals over generations and may cause various forms of disease severity, impacting life expectancy and quality of life.

Evolution of Proteins

Significance of Protein and Nucleic Acid Sequences:

Analyzing protein and nucleic acid sequences is pivotal in understanding the evolutionary relationships and functional adaptations of proteins over time.

Evolutionary Concepts:

  • Divergent Evolution: Accumulated mutations from a common ancestor result in protein modifications, leading to adaptations in different species that preserve certain fundamental functions.

  • Convergent Evolution: Different ancestral lineages independently evolve similar traits or functions, often through similar random mutations, which may be deleterious, neutral, or beneficial.

Pentraxins in Innate Immunity

Pentraxins:

Pentraxins are vital components of the innate immune system, serving to identify and target cellular debris and pathogens.

Examples:

  • C-Reactive Protein (CRP): Produced by the liver in response to inflammation.

  • Serum Amyloid P (SAP): Binds to damaged tissues and pathogens, functioning in immune responses.

  • Limulus polyphemus (horseshoe crab): Despite the absence of an adaptive immune system, it produces pentraxins that share structural similarities with human pentraxins, indicating functional conservation through evolution, exhibiting 32% sequence identity with Limulus and 51% with human pentraxins due to gene duplication events.

Relationship Between Sequence, Structure, and Function

Homology and Functionality:

Proteins that demonstrate sequence homology are likely to exhibit structural similarities and similar functions, supporting the evolutionary narrative.

Example:

  • Cytochrome C: A small, vital protein with 104 residues, it plays critical roles in cellular respiration.

  • Key Residues: Important for heme binding—key invariant residues include met-80, his-18, cys-22, and cys-25.

Sequence Homology Examples:

A comparative analysis across various species highlights differing degrees of sequence identity, providing insights into evolutionary relationships.

Functions without Homology

Similarity in Functions:

Certain proteins can perform analogous functions without possessing structural or sequence homology due to convergent evolutionary pressures.

Example:

  • Subtilisin (a bacterial serine proteinase) and Chymotrypsin (a mammalian serine proteinase): While they perform similar enzymatic functions, they exhibit significant differences in their structures; both proteins share a common catalytic triad composed of aspartate (Asp), histidine (His), and serine (Ser).

Structural Homology without Sequence Homology

Structural Homology:

It is possible for proteins to share similar structural characteristics while displaying no sequence resemblance or identical functions.

Example:

  • Triose Phosphate Isomerase and 3-Dehydroquinase: Both exhibit barrel structures yet participate in disparate metabolic pathways.

Functional Similarity Despite Low Sequence Identity

Low Sequence Identity:

Some proteins can maintain similar folded conformations and perform analogous biological functions despite showing low overall sequence identity.

Example:

  • Lactate Dehydrogenase (LDH) and Alcohol Dehydrogenase (ADH): Both proteins share identical folds and NAD binding capabilities, illustrating functional similarities across distinct sequences.

Protein Sequencing Techniques

Edman Degradation:

This method provides a means to determine the amino acid sequence of proteins through progressive cycles of reactions involving phenyl isothiocyanate.

Limitations:

  • Involves identifying only 10-20 residues, making it labor-intensive.

  • Utilization of automated methods is often preferred for direct gene sequencing, offering more comprehensive insights into protein structure formation.

Cleavage Processes in Proteins

Efficiency Considerations:

An overview of a cleavage process is provided with the expectation of an 80% efficiency rate, illustrating how proteins can be effectively cleaved into functional fragments conducive for research and analysis.

Summary

Overview:

This document recaps critical concepts related to protein structure. It underscores the intricate relationships that exist between sequence, structure, function, and the perspectives of evolution, advancing our understanding of biochemical processes, health implications from genetic diseases, and the evolutionary significance of proteins.