The series of deaths which led to Charles V to become the "Universal Emperor" is quite, very, extraordinarily unlikely. So lets say that someone survives in that long line of infant mortality, insanity, and just plain bad luck, and Charles, he may not become the Fifth, is just the heir to his father, and thus the Hapsburgs, who stay an HRE only dynasty.
Now I think that Charles V can still be elected Holy Roman Emperor over his chief rival, the King of France Francis I, after his grandfather's death (his father pre-deceased his grandfather, maybe this gets butterflied, maybe not) even without direct access to the American gold that he was able to purchase the election with OTL.
Charles was raised in what had been the Duchy of Burgundy, one of the cradles of Humanism, and I think that if his strategic situation were changed, i.e. were he not King of Spain and Naples, then he would be able to see the huge political benefits that Protestantism had. I mention his upbringing because a lot of that Humanist thinking, from Erasmus for instance, is very proto-Protestant.
So Charles V, instead of trying to destroy Protestantism, could take a much more Henry VIII kind of approach, using the wealth of the church to secure the Imperial throne, and build up Imperial institutions. With high-level, Imperial control of the Reformation, it may be just that, a Reformation of the Catholic Church, taking the Reformation on a historical pathway totally alien from OTL. I think that Protestantism in Germany tapped into a kind of proto-nationalism, and that feeling could be harnessed by an intelligent and properly positioned Emperor.
Charles V, the last Emperor to be crowned by the Pope, and the first Emperor to truly rule the Empire.
Thoughts?