https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021871/
The Role of the Transmembrane RING Finger Proteins in Cellular and Organelle Function
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A
large number of RING finger (RNF) proteins are present in eukaryotic
cells and the majority of them are believed to act as E3 ubiquitin
ligases. In humans, 49 RNF proteins are predicted to contain
transmembrane domains, several of which are specifically localized to
membrane compartments in the secretory and endocytic pathways, as well
as to mitochondria and peroxisomes. They are thought to be molecular
regulators of the organization and integrity of the functions and
dynamic architecture of cellular membrane and membranous organelles.
Emerging evidence has suggested that transmembrane RNF proteins control
the stability, trafficking and activity of proteins that are involved in
many aspects of cellular and physiological processes. This review
summarizes the current knowledge of mammalian transmembrane RNF
proteins, focusing on their roles and significance.
.. The human genome encodes approximately 300 RNF proteins, many of which
are soluble proteins with a variety of cellular functions, including
oncogenesis, development, signal transduction, the cell cycle and
apoptosis. According to recent reports [19,20,21]
and data base mining, at least 49 RNF proteins have hydrophobic regions
predicted to be transmembrane domains, implying that they are embedded
in the cellular membrane and directly participate in the biological
processes of both the cellular membrane and membranous organelles. This
review summarizes current knowledge of the transmembrane RNF proteins in
mammals and discusses their significance in terms of organelle function
and morphology.
Phylogenetic
analysis of putative human transmembrane RNF proteins. The tree was
constructed by the neighbor-joining method with ClustalW [22] and MEGA4 [23]
using 5,000 bootstrap resamplings. The scale bar indicates 0.2 amino
acid substitutions per each amino acid position. Members of the TRIM,
PA-TM-RING, MARCH and RBR families are indicated in green, red, blue and
purple fonts, respectively.
- A phylogenetic tree analysis indicated that more than half of the human transmembrane RNF proteins are grouped into a small number of structurally related clans, which include members of the tripartite motif-containing (TRIM),
- PA-TM-RING,
- RING between RNFs (RBR) and
- membrane-associated RING-CH (MARCH) families (Figure 2).
Moderate sequence homology is observed between RMA1/RNF5 and RNF185
(∼60%) and between RNF121 and RNF175 (∼71%). The rest share little
sequence homology, with the exception of the RNF domain, suggesting
their diverse subcellular localization and functions.
2.1. The TRIM Family Members
TRIM
proteins [also termed RNF, B box and coiled-coil (RBCC) proteins] are
comprised of a group of proteins containing three characteristic
structures, the RING-HC finger domain followed by one or two B-box
domains and a coiled-coil region (Figure 3). There are more than 60 human TRIM proteins, several of which can act as E3 enzymes [24].
TRIM proteins have a single type 2 B-box (B-box2) or tandem type 1 and
type 2 B-boxes. The B-boxes are zinc-finger-like motifs with the
consensus sequences C5(C/H)H2 (type 1) and CHC(D/C)C2H2 (type 2), which
bind two zinc ions in a cross-brace manner similar to the RING domain.
The structural similarity suggests that the B-boxes and RNF domains have
evolved from a common ancestor [25].
Although no clear function of the B-box domain has as yet been
identified, its positioning close to the RNF domain suggests that the
B-box domain may modify E3 activity. The coiled-coil regions are
important for the subcellular localization and oligomerization of TRIM
proteins [26].
TRIM proteins are grouped into two classes based on the structures of
their C-terminal extensions: one group has an SPRY domain of unknown
function and the other group has a variety of domain structures [27].
The Ret finger protein (RFP)2/TRIM13/Leu5/RFN77 and TRIM59/RNF104
belong to the latter group, and do not have any obvious domain structure
apart from the hydrophobic regions (Figure 3).
2.2. The PA-TM-RING Family Members
The
PA-TM-RING family is defined by three conserved domains, the
protease-associated (PA) domain, the transmembrane domain and the
RING-H2 finger domain (Figure 3) [30,31].
The PA-TM-RING family is comprised of 9 proteins [Goliath/RNF130, gene
related to anergy in lymphocytes (GRAIL)/RNF128, RNF133, RNF148, RNF149,
RNF150, RNF167, RNF13 and zinc and ring finger 4 (ZNRF4)/Nixin/RNF204],
and most of them possess apparent signal peptide sequences at their
N-termini (Figure 3).
RNF122 is an anomalistic member of the PA-TM-RING family, in that it
lacks both the signal peptide sequence and PA domain. PA-TM-RING
proteins are unique in containing an extracellular or luminal domain (Figure 3). The extracellular or luminal PA domain is also found in several receptors and peptidases in yeast, metazoans and plants [32].
The PA domain is proposed to serve as a protein–protein interaction
module. Indeed, the PA domain of GRAIL facilitates the recognition of
and binding to its substrate proteins (i.e., CD154/CD40L and CD83) [33,34]. RNF13 has a nuclear localization signal in the C-terminal region flanking the transmembrane domain [35].
2.2. The PA-TM-RING Family Members
The
PA-TM-RING family is defined by three conserved domains, the
protease-associated (PA) domain, the transmembrane domain and the
RING-H2 finger domain (Figure 3) [30,31].
The PA-TM-RING family is comprised of 9 proteins [Goliath/RNF130, gene
related to anergy in lymphocytes (GRAIL)/RNF128, RNF133, RNF148, RNF149,
RNF150, RNF167, RNF13 and zinc and ring finger 4 (ZNRF4)/Nixin/RNF204],
and most of them possess apparent signal peptide sequences at their
N-termini (Figure 3).
RNF122 is an anomalistic member of the PA-TM-RING family, in that it
lacks both the signal peptide sequence and PA domain. PA-TM-RING
proteins are unique in containing an extracellular or luminal domain (Figure 3). The extracellular or luminal PA domain is also found in several receptors and peptidases in yeast, metazoans and plants [32].
The PA domain is proposed to serve as a protein–protein interaction
module. Indeed, the PA domain of GRAIL facilitates the recognition of
and binding to its substrate proteins (i.e., CD154/CD40L and CD83) [33,34]. RNF13 has a nuclear localization signal in the C-terminal region flanking the transmembrane domain [35].
.3. The MARCH Family Members
There are only 11 proteins containing the RING-CH finger domain in humans and they are all contained in the MARCH family [36].
As the name membrane-associated RING-CH suggests, the MARCH proteins
are integrated into the cellular membrane, with the exception of the two
members MARCH7/RNF177 and MARCH10/RNF190, which have no transmembrane
domain [37,38].
Two-transmembrane type MARCH proteins contain putative PDZ
domain-binding motifs at their C-termini (type I: S/T-X-Φ; type II;
Φ-X-Φ; type III; D/E-X-Φ; type IV; X-Ψ-D/E, where Φ and Ψ represent
hydrophobic and aromatic residues, respectively) [39].
PDZ domains are protein–protein interaction modules often found in
scaffold proteins. Binding to the PDZ domain facilitates the
trafficking, localization and assembly of membrane proteins such as
receptors, ion channels and transporters. The PDZ-binding motif is also
found in several other transmembrane RNF proteins [19].
The N-terminal regions of MARCH4/RNF174, MARCH9/RNF179 and MARCH11
contain proline-rich sequences, which mediate protein–protein
interactions (Figure 3) [40].
2.4. The RBR Family
The RBR family is characterized by the RBR signature, which consists of two RNFs linked by an in-between-ring (IBR) domain (Figure 3) [41].
While the N-terminal RNF (RING1 or N-RING) forms a canonical
cross-brace structure, the C-terminal RNF (RING2 or C-RING) has a
different tertiary structure, binding one metal ion [42].
This structural difference suggests that the two RNF domains are
functionally different. The IBR domain comprises two zinc-binding
structures in a C6HC configuration. It is established that
the RING1 domain is a central hub of the E3 Ub ligase activity. In some
cases, the IBR and RING2 are required for the correct E3 functions by
their role in mediating protein–protein interactions with E2 enzymes and
substrate proteins [41].
A large number of RBR proteins are found in eukaryotes from yeast to
humans that have a diverse range of biological functions, including
protein quality control, signaling, cell cycle and apoptosis [41].
Among the human RBR proteins, 5 proteins (Dorfin/RNF19A, RNF19B/IBRDC3,
RNF144A, RNA144B/IBRDC2/p53RFP and RNF217/IBRDC1) have hydrophobic
regions (Figure 3), but their membrane insertion sites have not yet been determined.
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