PROSITE documentation PDOC00449

Zinc finger RING-type signature and profile

A number of eukaryotic and viral proteins contain a conserved cysteine-rich domain of 40 to 60 residues (called C3HC4 zinc-finger or 'RING' finger) [1] that binds two atoms of zinc. There are two different variants, the C3HC4-type and the C3H2C3-type, which is clearly related despite the different cysteine/histidine pattern. The latter type is sometimes referred to as "RING-H2 finger".

The 3D structure [2] of the zinc ligation system is referred to as the "cross-brace" motif. This atypical conformation is also shared by the FYVE (see <PDOC50178>) and PHD (see <PDOC50016>) domains. The way the "cross-brace" motif is binding two atoms of zinc is illustrated in the following schematic representation:

                               x x x     x x x
                              x      x x      x
                             x        x        x
                            x        x x        x
                           C        C   C        C
                          x  \    / x   x \    /  x
                          x    Zn   x   x   Zn    x
                           C /    \ C   H /    \ C
                           x         x x         x
                  x x x x x x         x         x x x x x x

'C': conserved cysteine involved zinc binding.
'H': conserved histidine involved in zinc binding.
'Zn': zinc atom.

Many proteins containing a RING finger play a key role in the ubiquitination pathway. The ubiquitination pathway generally involves three types of enzyme, know as E1, E2 and E3. E1 and E2 are ubiquitin conjugating enzymes. E1 acts first and passes ubiquitin to E2. E3 are ubiquitin protein ligases, responsible for substrate recognition. It has been shown [3,4] that several RING fingers act as E3 enzymes in the ubiquitination process.

Some proteins known to include a RING finger are listed below:

• Mammalian V(D)J recombination activating protein (gene RAG1). RAG1 activates the rearrangement of immunoglobulin and T-cell receptor genes.
• Mouse rpt-1. Rpt-1 is a trans-acting factor that regulates gene expression directed by the promoter region of the interleukin-2 receptor α chain or the LTR promoter region of HIV-1.
• Human rfp. Rfp is a developmentally regulated protein that may function in male germ cell development. Recombination of the N-terminal section of rfp with a protein tyrosine kinase produces the ret transforming protein.
• Human 52 Kd Ro/SS-A protein. A protein of unknown function from the Ro/SS-A ribonucleoprotein complex. Sera from patients with systemic lupus erythematosus or primary Sjogren's syndrome often contain antibodies that react with the Ro proteins.
• Human histocompatibility locus protein RING1.
• Human PML, a probable transcription factor. Chromosomal translocation of PML with retinoic receptor α creates a fusion protein which is the cause of acute promyelocytic leukemia (APL).
• Mammalian breast cancer type 1 susceptibility protein (BRCA1).
• Mammalian cbl proto-oncogene.
• Mammalian bmi-1 proto-oncogene.
• Vertebrate CDK-activating kinase (CAK) assembly factor MAT1, a protein that stabilizes the complex between the CDK7 kinase and cyclin H (MAT1 stands for 'Menage A Trois').
• Mammalian mel-18 protein. Mel-18 which is expressed in a variety of tumor cells is a transcriptional repressor that recognizes and bind a specific DNA sequence.
• Mammalian peroxisome assembly factor-1 (PAF-1) (PMP35), which is somewhat involved in the biogenesis of peroxisomes. In humans, defects in PAF-1 are responsible for a form of Zellweger syndrome, an autosomal recessive disorder associated with peroxisomal deficiencies.
• Xenopus XNF7 protein, a probable transcription factor.
• Trypanosoma protein ESAG-8 (T-LR), which may be involved in the postranscriptional regulation of genes in VSG expression sites or may interact with adenylate cyclase to regulate its activity.
• Drosophila proteins Posterior Sex Combs (Psc) and Suppressor two of zeste (Su(z)2). The two proteins belong to the Polycomb group of genes needed to maintain the segment-specific repression of homeotic selector genes.
• Drosophila protein male-specific msl-2, a DNA-binding protein which is involved in X chromosome dosage compensation (the elevation of transcription of the male single X chromosome).
• Arabidopsis thaliana protein COP1 which is involved in the regulation of photomorphogenesis.
• Fungal DNA repair proteins RAD5, RAD16, RAD18 and rad8.
• Herpesviruses trans-acting transcriptional protein ICP0/IE110. This protein which has been characterized in many different herpesviruses is a trans- activator and/or -repressor of the expression of many viral and cellular promoters.
• Baculoviruses protein CG30.
• Baculoviruses major immediate early protein (PE-38).
• Baculoviruses immediate-early regulatory protein IE-N/IE-2.
• Caenorhabditis elegans hypothetical proteins F54G8.4, R05D3.4 and T02C1.1.
• Yeast hypothetical proteins YER116c and YKR017c.

We developed a pattern that specifically recognized the C3HC4-type. We also developed a profile for C3HC4-type and RING-H2 type.