Ras-related protein Ral-B (RalB) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''RALB''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
on chromosome 2.
This protein is one of two
paralog
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
s of the Ral protein, the other being
RalA, and part of the
Ras GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a ...
family.
RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.
Its biological role thus implicates it in many
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s.
Structure
The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example,
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
of Serine 194 on RalA by the
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
Aurora A results in the relocation of RalA to the
inner mitochondrial membrane
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
, where RalA helps carry out
mitochondrial fission
Mitochondrial fission is the process by which mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by mitochondrial fusion, where two mitochondria fuse together to form a larger one. Fu ...
; whereas phosphorylation of Serine 198 on RalB by the kinase
PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function.
Function
RalB is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.
As a Ras GTPase, RalB functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalB can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes.
For instance, RalB interacts with two components of the
exocyst The exocyst is an octameric protein complex involved in vesicle trafficking, specifically the tethering and spatial targeting of post- Golgi vesicles to the plasma membrane prior to vesicle fusion. It is implicated in a number of cell processes, in ...
,
Exo84 and
Sec5, to promote
autophagosome
An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, i ...
assembly, secretory vesicle trafficking, and tethering. Other downstream biological functions include
exocytosis
Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...
,
receptor-mediated endocytosis
Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This ...
,
tight junction
Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein Cell junction, junctional complexes between epithelial cells, sealing and preventing leakage of solutes and water. Th ...
biogenesis,
filopodia
Filopodia (: filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lamellipod ...
formation, mitochondrial fission, and
cytokinesis
Cytokinesis () is the part of the cell division process and part of mitosis during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division ...
.
While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalB is more involved in apoptosis and cell motility.
Moreover, RalB specifically interacts with Exo84 to assemble the beclin-1–VPS34 autophagy initiation complex, and with Sec5 to activate the innate immune response via the Tank-binding kinase 1 (
TBK1).
Clinical significance
Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.
Though the exact mechanisms remain unclear, studies reveal that RalB promotes tumor invasion and metastasis. As a result, inhibition of RalB inhibits further progression of cancer.
In addition, RalB regulates p53 levels in a K-Ras-independent manner during cancer development.
RalB also promotes cell survival during infection by double-stranded DNA viruses by activating TBK1 to carry out an immune response.
Interactions
RalB has been shown to
interact with:
*
CDC42
Cell division control protein 42 homolog (Cdc42 or CDC42) is a protein that in humans is encoded by the ''CDC42'' gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in ''S. cerevisiae'' (yeast) as a mediator of ...
,
*
EXOC8
Exocyst complex component 8 is a protein that in humans is encoded by the ''EXOC8'' gene.
Interactions
EXOC8 has been shown to interact with RALB
Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the ''RALB'' gene ...
,
*
RALBP1
RalA-binding protein 1 is a protein that in humans is encoded by the ''RALBP1'' gene.
Interactions
RALBP1 has been shown to Protein-protein interaction, interact with:
* Cyclin B1,
* HSF1,
* RALA,
* RALB, and
* REPS2.
References
Furt ...
,
References
Further reading
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