4.4: Protein with Alpha, Alpha-Beta, Beta and Little Secondary Structure

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Learning Goals (ChatGPT o1, 1/26/55)

• Classify Protein Structural Classes:

  • Distinguish between the three major classes of proteins based on secondary structure: α proteins, β proteins, and α/β proteins.
  • Identify examples of each class using representative models (e.g., orthogonal and updown bundles for α proteins, roll and sandwich for β proteins, and two- or three-layer sandwiches for α/β proteins).

• Analyze Specific Structural Motifs:

  • Describe the characteristics and functional roles of common motifs, such as:
    • The alpha-loop-alpha motif (e.g., helix-turn-helix and EF-hand) in DNA-binding and calcium-binding proteins.
    • The beta-hairpin (or beta-turn) motif found in antiparallel beta structures.
    • The Greek key motif as a recurring pattern in antiparallel beta sheets.
    • The beta-alpha-beta motif as a connector between parallel beta strands.
  • Use interactive 3D models and topology maps to visualize how these motifs are arranged and how they contribute to the overall protein fold.

• Understand Structural Motifs in Protein Architecture:

  • Explain how super-secondary structures (motifs) are integrated into larger architectural frameworks (domains) that determine the protein's tertiary structure.
  • Illustrate how the arrangement of motifs such as the Rossmann fold and TIM barrel relates to cofactor binding and enzymatic activity.
  • Discuss how proteins with little secondary structure, like HIV-1 TAT or metallothionein, may undergo conformational changes upon binding their targets.

• Connect Structure to Function:

  • Analyze how the distribution of secondary structures within a protein (e.g., extensive α-helices in globular proteins versus β-sheet-dominated proteins) influences its overall shape, stability, and biological function.
  • Evaluate the functional significance of amphipathic helices and beta propellers in processes such as membrane integration and molecular recognition.

• Apply Bioinformatics Tools to Structural Classification:

  • Explore databases and tools (e.g., CATH) to understand how proteins are classified into structural classes based on secondary and tertiary structure.
  • Compare structural motifs across proteins with similar functions to infer evolutionary relationships and predict functional sites.

These learning goals are designed to provide a framework for understanding how common structural motifs contribute to protein architecture and ultimately to the diverse functions of proteins in biological systems.

Proteins can also be classified according to the type and extent of secondary structure found in the protein. A detailed description of protein classes can be found at CATH. Here, we will describe the basic types with a few examples.

Alpha proteins

The core of these proteins is composed of alpha helices. The CATH classification shows two major types

a. Orthogonal bundles. Example: the Z[beta] Domain of the RNA-editing Enzyme ADAR1 (1xmk), shown in the interactive iCn3D model in Figure \(\PageIndex{1}\).

Figure \(\PageIndex{1}\): Alpha protein, Orthogonal bundles: Z[beta] Domain of the RNA-editing Enzyme ADAR1 (1xmk) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...fxHFM9ErUptjY7

b. Updown bundles. Example: Phospholipase A2 from Agkistrodon acutus venom (1mc2), shown in the interactive iCn3D model in Figure \(\PageIndex{2}\).

Figure \(\PageIndex{2}\): Alpha protein, Updown bundles: Phospholipase A2 from Agkistrodon acutus venom (1mc2) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...NGSeK9JAMe3Qh9

Beta proteins

In these proteins, the core is typically antiparallel beta sheets. There are many types of these, including single sheets, rolls, beta barrels, clams, sandwiches, propellers, etc (some of which we have already discussed). Here are a few interesting examples.

a. Roll. Example: The second SH3 domain from ponsin (2O9S), shown in the interactive iCn3D model in Figure \(\PageIndex{3}\).

Figure \(\PageIndex{3}\): Beta protein Roll: Second SH3 domain from ponsin (2O9S), (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...xYZBXHWpt3njf7

b. Sandwich. Example: Mcg immunoglobulin light chain variable domain (4unu), shown in the interactive iCn3D model in Figure \(\PageIndex{4}\).

Figure \(\PageIndex{4}\): Beta protein Sandwich - Mcg immunoglobulin light chain variable domain (4unu) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...4vcY5svrBveJp7

Alpha/Beta proteins

These are the most common class and contain many beta-alpha-beta motifs with mostly parallel beta strands surrounded by alpha helices. Again, these proteins have many variants, including the alpha-beta barrel. We will show two other common ones.

a. Two-layer sandwich. Example: HIV-1 Nef-SF2 Core Domain (4U5W), shown in the interactive iCn3D model in Figure \(\PageIndex{5}\).

Figure \(\PageIndex{5}\): Alpha-Beta Two layer sandwich - HIV-1 Nef-SF2 Core Domain (4U5W) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...6Fx6J3ecPJbF3A

b. Three-layer sandwich (aba). Example: Human biliverdin IX beta reductase (1hdo), shown in the interactive iCn3D model in Figure \(\PageIndex{6}\).

Figure \(\PageIndex{6}\): Alpha-Beta Three layer sandwich (aba) - Human biliverdin IX beta reductase (1hdo) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...s8GrdasiecmZC8

Little Secondary Structures

These proteins most likely can adopt different conformations on binding to target molecules. Here are two examples

a. HIV-1 TAT (Transactivating) Protein (1JFW), shown in the interactive iCn3D model in Figure \(\PageIndex{7}\).

Figure \(\PageIndex{7}\): Few Secondary Structures - HIV-1 TAT (Transactivating) Protein (1JFW) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...zVYofj3HFasWBA

b. Rat rat metallothionein-2 (4MT2), shown in the interactive iCn3D model in Figure \(\PageIndex{8}\).

.

Figure \(\PageIndex{8}\): Few Secondary Structures - Rat rat metallothionein-2 (4MT2) (Copyright; author via source).
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...fYY4xF2RWd7pD7

Summary

This chapter provides a comprehensive overview of the recurring structural motifs and architectures that form the building blocks of protein structure. Although each protein’s 3D structure is unique, many share common substructures that appear repeatedly across different protein families and are often linked to specific functions.

The discussion begins with super-secondary structures, which are groups of secondary structure elements organized in characteristic patterns. Key motifs include:

• Alpha-Loop-Alpha Motifs:
  These motifs, exemplified by the helix-turn-helix in DNA-binding proteins (e.g., the basic helix-turn-helix of c-Myc) and the EF-hand found in calcium-binding proteins like calmodulin, involve two alpha helices connected by a loop. In the EF-hand, the loop is enriched in acidic and polar residues that coordinate calcium ions, creating a “hand” that grips the ion.

• Beta-Hairpins and Greek Key Motifs:
  The beta-hairpin, a simple turn connecting two antiparallel beta strands, and the more elaborate Greek key motif, which organizes four adjacent beta strands in a distinctive pattern, are common in beta-rich proteins. These motifs provide the structural foundation for larger beta-sheet arrangements, such as rolls, sandwiches, and propellers.

• Beta-Alpha-Beta Motifs:
  This motif connects two beta strands with an intervening alpha helix, forming a common structural framework in many enzymes. It plays a crucial role in defining the active sites and overall fold of proteins like triose phosphate isomerase.

The chapter then shifts to the higher-order organization of protein structure, discussing how these recurring motifs are integrated into larger structural architectures or domains. Examples include:

• The Rossmann Fold:
  A ubiquitous motif that binds nucleotide cofactors (such as NAD⁺) through a distinctive beta-alpha-beta arrangement, forming a three-layered sandwich.

• The TIM Barrel:
  A common and versatile fold characterized by eight alternating alpha helices and parallel beta strands, which serves as the scaffold for a variety of enzyme families despite low sequence similarity among them.

• Beta Helices and Beta Propellers:
  Beta helices form right-handed, parallel helical structures that are often found in proteins from pathogens, while beta propellers consist of multiple blade-shaped beta sheets arranged radially around a central axis, forming a funnel-shaped binding site.

Finally, the concept of domains is introduced as the fundamental units of tertiary structure that fold independently and often serve as the functional modules of proteins. The chapter discusses how domains arise through evolutionary processes such as duplication, divergence, and recombination, and how modern computational tools (like TED, CATH, and Pfam) are used to classify and predict domain structures across the proteome.

In summary, this chapter illustrates that despite the complexity of protein structures, a relatively limited set of structural motifs and architectures recur across different proteins, providing insight into their function, evolution, and the principles governing protein folding and assembly.