John Hay
John Hay Biomedical
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Rough draft.This research track is under review with Dr. Atit's lab. Content and sequence may still change.
The Baby Mateo Case
Genetics domainMedical Interventions (MI), with PBS overlapLesson 10 of 20Your seat: Protein scientist

What the IRF6 Protein Looks Like

Discovery question

What does the IRF6 actually look like?

💡 A 's shape determines its job, so where a variant lands on the protein predicts what job it breaks.

The plan

Prerequisite check

Before this page, you should know
  • A changes the sequence; a changes a control region and alters how much protein is made, without changing the sequence.
  • IRF6 has an called MCS-9.7 about 10 kb where the AP-2alpha (TFAP2A) normally docks to switch IRF6 on.
Today's new idea is only
A 's shape determines its job, so where a variant lands on the protein predicts what job it breaks.
Learn first

What you will learn

Goal: Students will describe the IRF6 's two-domain architecture (a and a protein-binding SMIR/IAD domain) and explain why a variant's domain location predicts its effect.

Know by the end
  • A is a part of a that folds on its own and does a specific job.
  • IRF6 (467 amino acids) has a (residues 7 to 115, a winged-helix fold) and a C-terminal -binding (SMIR/IAD) domain, joined by a disordered linker (residues 121 to 156).
  • changes are statistically enriched in the but not the .
  • means a 's shape determines its job, so a variant's domain location predicts what job it breaks; a truncating change deletes whichever domains come after the cut.
Learn first

Model: The IRF6 domain map, and the same variant data placed on it

IRF6 is a 467 amino acids long that folds into two main working parts, called domains, joined by a floppy linker (real positions from UniProt O14896). The (DBD), residues 7 to 115, is a winged helix-turn-helix shape that physically clamps onto DNA so IRF6 can switch target genes on; it is encoded by exons 3 to 4. The (SMIR / IAD) is C-terminal and links IRF6 to partner proteins so it can act as a team; it is encoded by exons 7 to 9. A disordered linker (residues 121 to 156) connects the two. R84 lives inside the DNA-binding domain.

Now place the Lesson 8 variants as positions on the map: R84C / R84H sit in the (residue 84) and abolish DNA binding (), causing severe PPS. L22P sits in the DNA-binding domain (residue 22) and abolishes DNA binding, causing VWS. S424L sits in the and decreases transcriptional activity, causing PPS. A truncating change (e.g. R250X) cuts the chain so the domains past the cut are lost, causing and VWS. The big reported pattern: changes are enriched in the DNA-binding domain but not the protein-binding domain.

Read this in pieces, one chunk at a time
Do the work

Explore (work the model before reading on)

  1. How long is the IRF6 , and what are its two main domains?
  2. Which domain does residue 84 (the R84C hotspot) fall inside?
  3. What is the reported effect of variants in the (R84C, L22P)?
  4. changes pile up in the , and that domain's job is to grab DNA. Why would a change there be especially likely to break IRF6's function?
  5. A truncating change at residue 250 removes everything after position 250. Which domain is lost when the chain is cut at 250, and what job goes with it?
  6. Imagine a new IRF6 in the floppy linker (around residue 140), far from both domains. Predict whether it is more or less likely to be damaging than R84C, and explain using .
  7. In one sentence, what pattern links a variant's DOMAIN location to its likely effect on the ?
The plan

Guided notes

1

What a domain is

Model start: A is a self-folding part of a that carries out a specific function.
  • A is a part of a that folds on its own and does a specific ____.
  • IRF6 has two domains joined by a floppy linker.
2

IRF6's two domains

  • The (residues 7 to ____): a winged helix that clamps onto ____ so IRF6 can switch target genes on; most damaging , including R84, land here.
  • The (SMIR / IAD, near the C-end): links IRF6 to ____ proteins so it can work as part of a team.
3

Structure-function

  • A 's shape determines its job, so WHERE a variant lands predicts WHAT job it breaks.
  • A change in the wrecks DNA gripping; a truncating change deletes whichever domains come ____ the cut.
Explore

Reading the Research

What to read
Read the title and the abstract only, not the whole paper. Leslie EJ, et al. 2012. IRF6 variants in VWS and PPS. Genet Med. [PMID:23154523]
Why this source matters
This is the published evidence behind today's idea: A 's shape determines its job, so where a variant lands on the protein predicts what job it breaks.
Words to unlock first
protein domainDNA-binding domainprotein-binding domainSMIR / IAD domainstructure-function
Reading moves
  1. Skim the title and abstract first to get the gist.
  2. Circle the one sentence that states the main claim.
  3. Box the evidence the authors give for that claim.
  4. Mark one sentence that confuses you, and move on.
Stop point
You do not need the methods or statistics yet. If a sentence is about lab technique or math you have not learned, mark it and skip it.
Your output
Write one claim-evidence sentence: what this source claims, and the one piece of evidence that backs it up.
Lab day

Using the database (what to capture)

Part of today's expected outcome is to actually open the tool below and write down the value it gives you. That captured value is the evidence you will use in your Claim, Evidence, Reasoning. Follow the steps, use the labeled screenshot so you do not get lost, and record each field.

UniProt
Open the tool

The reference record for a : its length, its domains, and what each part does.

When you use this: Use this when you need to know which PART of the a variant hits, so you can predict whether it breaks a working region.
What the screen looks like
uniprot.org/uniprotkb/O14896 IRF6 human 1 Protein entry: IRF6 2 Length + domains 467 aa · DNA-binding + SMIR domains 3 1 Open the IRF6 entry (O14896). 2 Go to the Family & Domains section. 3 Read the length and which domains exist.
A labeled map of the screen. The circled numbers match the steps.
Step by step
  1. 1Open uniprot.org and search IRF6 human, then open entry O14896.
  2. 2Scroll to the Family and Domains section.
  3. 3Read the length and which domains exist (for example the ).
Capture these fields
  • Accession (the protein's ID): O14896
  • Length (amino acids): 467 aa
  • Domains / regions: A DNA-binding domain and a protein-partner (SMIR) domain
How to read it: The domains tell you which part of the does which job. A variant that lands inside the is more likely to break IRF6's -factor function than one in a spacer region.
Lost? UniProt help: reading protein domains
Where this fits
Tested on (Ohio WebXam)
Genetics of Disease · 072130
PLTW lesson
MI · Genetics domain · Unit 4 When Organs Fail, 4.1 Manufacturing Human Proteins (protein structure)
WebXam domain
Bio-Molecular Technology
Evidence to produce
Place three relatives' variants on the IRF6 domain map (a missense at residue 60, a missense at residue 424, and a nonsense at residue 100) and predict the consequence in one sentence each, naming the domain hit or lost and the job affected.
Lab / skill
Medical Interventions (MI) · Principles of Biomedical Science (PBS)
Words

Vocabulary (the same words your classes use)

SMIR / IAD domain
Explore

Vetted readings for this lesson

The plan

Track your progress today

Check these off as you work through the lesson, then submit. This tells Mr. Mendoza how you're doing so he can help the class. It does not replace turning in your producible.

Use the code Mr. Mendoza gave you, not your name. Saved on this device.

Check off as you finish
  • Read the Model and answered the Explore questions.
  • Filled in the guided notes in my own words.
  • Defined the new vocabulary with an example.
  • Opened UniProt and recorded the value it gave me.
  • Built the producible: Place three relatives' variants on the IRF6 domain map (a missense at residue 60, a missense at residue 424, and a nonsense at residue 100) and predict the consequence in one sentence each, naming the domain hit or lost and the job affected.
  • Wrote my Claim, Evidence, and Reasoning exit ticket.
Pick your period and code first.
See the grading rubric
See an example of today's finished work, and a WebXam practice questionA worked model of the producible plus one exam-style item with the answer and full rationale.
Check yourself

Exit ticket (Claim, Evidence, Reasoning)

  • Claim: A variant's domain location helps predict ____.
  • Evidence: In IRF6, changes are enriched in the ____ domain, where the 's job is to ____.
  • Reasoning: Therefore knowing the domain map matters because ____.
How this is graded (rubric)
For: Place three relatives' variants on the IRF6 domain map (a missense at residue 60, a missense at residue 424, and a nonsense at residue 100) and predict the consequence in one sentence each, naming the domain hit or lost and the job affected.
CriterionProficientDevelopingBeginning
CompleteEvery required part of the artifact is present and filled in.Most parts are present, but one is missing or left blank.Several parts are missing.
AccurateThe science and data are correct and match the evidence.Mostly correct, with a small factual slip.Key science or data is wrong.
Scientific reasoning (CER)States a claim, backs it with specific evidence, and explains the reasoning.Has a claim and evidence, but the reasoning is thin or missing.Gives an answer with no evidence or reasoning.
Professional communicationClear, organized, and labeled the way a clinician or scientist would write it.Readable but disorganized or missing labels.Hard to follow.
SubmittedTurned in the right way (Schoology for routine work) and confirmed.Turned in, but in the wrong place or unconfirmed.Not turned in.
How the model answer scores against this rubric
  • CompleteProficient: Nothing is left blank: the model fills every part of "Place three relatives' variants on the IRF6 domain map (a missense at residue 60, a missense at residue 424, and a nonsense at residue 100) and predict the consequence in one sentence each, naming the domain hit or lost and the job affected.".
  • AccurateProficient: Every number and claim matches the case evidence.
  • Scientific reasoning (CER)Proficient: It names a claim, cites the specific evidence, and explains the reasoning, not just the answer.
  • Professional communicationProficient: It is organized and labeled like a real chart note.
  • SubmittedProficient: It would be turned in on Schoology and confirmed.
Explore

Where this leads: careers

Protein scientist / structural biologist Computational biologist Variant analyst

What's next: Our has critical domains. How can we tell which parts are so important that evolution never lets them change?

The Hidden Regulatory VariantIs This Gene Important Across Species?
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