Nondomain biopolymers: Flexible molecular strategies to acquire biological functions

Abstract

A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes the functional significance of biomolecules. These conserved sequences fold into distinct secondary and tertiary structures, enable highly specific molecular interactions, and regulate complex yet organized molecular processes within living cells. However, recent evidence suggests that biomolecules can also function through primary sequence regions that lack conservation across species or gene families. These regions typically do not form rigid structures, and their inherent flexibility is critical for their functional roles. This review examines the emerging roles and molecular mechanisms of "nondomain biomolecules," whose functions are not easily predicted due to the absence of conserved functional domains. We propose the hypothesis that both domain- and nondomain-type molecules work together to enable flexible and efficient molecular processes within the highly crowded intracellular environment.

Keywords: intrinsically disordered proteins; noncoding RNA; nondomain biopolymers; nonmembranous organelles; nuclear bodies; phase separation.

FIGURE 1

Concept of domain‐type biomolecules and nondomain‐type biomolecules. Highly conserved primary sequences typically fold into conserved structures and perform conserved functions. Under this dogma, the functions of biomolecules or regions with nonconserved sequences have often been underestimated. Nondomain‐type biomolecules represent a unique group of biomolecules whose functions may be less dependent on their primary sequences and defined structures.

FIGURE 2

Examples of nonmembranous organelles. (a) Examples of representative nuclear and cytoplasmic nonmembranous organelles. (b) Components of nonmembranous organelles, which typically contain RNA and proteins with distinct intrinsically disordered regions (IDRs).

FIGURE 3

Building of paraspeckles on architectural lncRNA Neat1. (a) A model of paraspeckle formation on NEAT1_2 lncRNA via phase separation. Functional RNA domains are shown by square brackets (top). These domains interact with specific paraspeckle proteins, including NONO and SFPQ, which assemble the core or putative shell‐forming proteins (middle). Multivalent interactions between IDRs of these proteins induce phase separation, leading to the construction of a massive paraspeckle structure (bottom). (b) Core–shell structure of paraspeckles observed under a super‐resolution microscope (left) and schematic drawing of the positions of each component in paraspeckle spheres (right). Images are reprinted from West et al. (2016).

FIGURE 4

Hero proteins provide an appropriate molecular milieu for various client proteins. (a) Identification of Hero proteins. Hero proteins were originally identified as proteins that assist in the elution of recombinant Ago protein from beads upon protease digestion. (b) Hero11 prevents the formation of cytoplasmic aggregates of TDP‐43 lacking the nuclear localization signal when co‐expressed in cells. (c) Structures of Hero proteins predicted with AlphaFold2. Note that they are highly intrinsically disordered.

FIGURE 5

Tardigrades' extreme resistance to harsh environments. (a) Scanning electron microscope images of a tardigrade (water bear) in both the living and tun‐state. Images are reprinted from Arakawa (2022). (b) Prediction of intrinsically disordered regions in tardigrade‐specific proteins associated with the tun‐state.

FIGURE 6

Molecular mechanisms of nondomain biopolymers. (a) A schematic model illustrating the multivalent interactions of nondomain biopolymers. (b) Typical molecular interactions involved in multivalent interactions. (c) Formation of molecular condensates by nondomain biopolymers. (d) Formation of specific structures by nondomain biopolymers upon binding to specific ligands. (e) Nondomain biopolymers function as hydrotropes or molecular shields for client proteins.